Heterocyclic compounds, methods for the preparation thereof, and uses thereof

ABSTRACT

The compounds of the present invention are of formula I: 
     
       
         
         
             
             
         
       
     
     wherein A, R 3 , R 4  is as defined herein, are useful as ligands for nicotinic receptors.

This application claims the benefit of U.S. Provisional application No.60/406,981, filed Aug. 30, 2002, the entire disclosure of which ishereby incorporated by reference.

FIELD OF THE INVENTION

The present invention relates generally to the field of ligands fornicotinic acetylcholine receptors (nAChR), activation of nAChRs, and thetreatment of disease conditions associated with defective ormalfunctioning nicotinic acetylcholine receptors, especially of thebrain. Further, this invention relates to novel compounds which act asligands for the α7nAChR subtype, e.g., anabaseine analogs, methods ofpreparing such compounds, compositions containing such compounds, andmethods of use thereof.

BACKGROUND OF THE INVENTION

There are two types of receptors for the neurotransmitter,acetylcholine: muscarinic receptors and nicotinic receptors, based onthe selectivity of action of muscarine and nicotine, respectively.Muscarinic receptors are G-protein coupled receptors. Nicotinicreceptors are members of the ligand-gated ion channel family. Whenactivated, the conductance of ions across the nicotinic ion channelsincreases.

Nicotinic alpha-7 receptor protein forms a homo-pentameric channel invitro that is highly permeable to a variety of cations (e.g., Ca⁺⁺).Each nicotinic alpha-7 receptor has four transmembrane domains, namedM1, M2, M3, and M4. The M2 domain has been suggested to form the walllining the channel. Sequence alignment shows that nicotinic alpha-7 ishighly conserved during evolution. The M2 domain that lines the channelis identical in protein sequence from chicken to human. For discussionsof the alpha-7 receptor, see, e.g., Revah et al. (1991), Nature, 353,846-849; Galzi et al. (1992), Nature 359, 500-505; Fucile et al. (2000),PNAS 97(7), 3643-3648; Briggs et al. (1999), Eur. J. Pharmacol. 366(2-3), 301-308; and Gopalakrishnan et al. (1995), Eur. J. Pharmacol.290(3), 237-246.

The nicotinic alpha-7 receptor channel is expressed in various brainregions and is believed to be involved in many important biologicalprocesses in the central nervous system (CNS), including learning andmemory. Nicotinic alpha-7 receptors are localized on both presynapticand postsynaptic terminals and have been suggested to be involved inmodulating synaptic transmission. It is therefore of interest to developnovel compounds, which act as ligands for the α7 nAChR subtype, for thetreatment of disease conditions associated with defective ormalfunctioning nicotinic acetylcholine receptors.

SUMMARY OF THE INVENTION

The present invention includes compounds of Formula I:

wherein

-   -   A is        -   (a) phenyl or pyridyl, each of which is substituted by a 5            to 7 membered heterocyclic ring containing an O, S, or N            ring atom, and optionally containing a further N ring atom,            wherein the heterocyclic ring is fully unsaturated,            partially saturated or fully saturated and is unsubstituted            or substituted one or more times by alkyl having 1 to 8            carbon atoms, halogenated alkyl having 1 to 8 carbon atoms,            hydroxyalkyl having 1 to 8 carbon atoms, alkenyl having 2 to            8 carbon atoms, alkynyl having 2 to 8 carbon atoms, alkoxy            having 1 to 8 carbon atoms, halogenated alkoxy having 1 to 8            carbon atoms, cycloalkyl having 3 to 10 carbon atoms (e.g.,            3 to 8 carbon atoms), cycloalkylalkyl having 4 to 14 carbon            atoms (e.g., 4 to 8 carbon atoms), Ar-alkyl wherein alkyl            portion has 1 to 8 carbon atoms (e.g., benzyl, phenethyl),            Het-alkyl wherein alkyl portion has 1 to 8 carbon atoms,            COR⁵, COOR⁵, CONR⁵R⁶, halogen, cyano, hydroxyl, NR¹R²,            nitro, oxo, thio, alkylthio (e.g., —S—CH₃), alkylsulfinyl            (e.g., —SO—CH₃), alkylsulfonyl (e.g., —SO₂—CH₃), Ar, Het or            combinations thereof, wherein the heterocyclic ring may be            bridged by a divalent alkylene group having 1 to 3 carbon            atoms (e.g., 2,5-diazabicyclo[2.2.1]hept-2-yl),            -   wherein said phenyl or pyridyl is optionally further                substituted by one or more substituents selected from                halogen, alkyl having 1 to 4 carbon atoms, alkoxy having                1 to 4 carbon atoms, NR¹R², nitro, hydroxyl, and cyano,                and            -   wherein said 5 to 7 membered heterocyclic ring is                optionally fused with an aryl group or heteroaryl group                which in each case contains 5 to 10 ring atoms and in                which the heteroaryl group contains 1 to 3 hetero atoms                each selected from O, S, and N, and wherein said aryl                group or heteroaryl group is optionally substituted one                or more times by alkyl having 1 to 8 carbon atoms,                halogenated alkyl having 1 to 8 carbon atoms,                hydroxyalkyl having 1 to 8 carbon atoms, alkenyl having                2 to 8 carbon atoms, alkynyl having 2 to 8 carbon atoms,                alkoxy having 1 to 8 carbon atoms, halogenated alkoxy                having 1 to 8 carbon atoms, cycloalkyl having 3 to 10                carbon atoms (e.g., 3 to 8 carbon atoms),                cycloalkylalkyl having 4 to 14 carbon atoms (e.g., 4 to                8 carbon atoms), Ar-alkyl wherein alkyl portion has 1 to                8 carbon atoms, Het-alkyl wherein alkyl portion has 1 to                8 carbon atoms, COR⁵, COOR⁵, CONR⁵R⁶, halogen, carboxy,                cyano, hydroxyl, NR¹R², nitro, oxo, thio, Ar, Het and                combinations thereof,        -   (b) phenyl or pyridyl which in each case is fused with a 5            to 7 membered heterocyclic ring containing 1 to 3 hetero            atoms each selected from O, S, and N, to form a bicyclic            group wherein the fused heterocyclic ring is fully            unsaturated, partially saturated or fully saturated, and            wherein said bicyclic group is unsubstituted or substituted            one or more times by alkyl having 1 to 8 carbon atoms,            halogenated alkyl having 1 to 8 carbon atoms, hydroxyalkyl            having 1 to 8 carbon atoms, alkenyl having 2 to 8 carbon            atoms, alkynyl having 2 to 8 carbon atoms, alkoxy having 1            to 8 carbon atoms, halogenated alkoxy having 1 to 8 carbon            atoms, cycloalkyl having 3 to 10 carbon atoms (e.g., 3 to 8            carbon atoms), cycloalkylalkyl having 4 to 14 carbon atoms            (e.g., 4 to 8 carbon atoms), COR⁵, COOR⁵, CONR⁵R⁶, halogen,            carboxy, cyano, hydroxyl, NR¹R², nitro, oxo, thio, alkylthio            (e.g., —S—CH₃), alkylsulfinyl (e.g., —SO—CH₃), alkylsulfonyl            (e.g., —SO₂—CH₃), Ar, Het, Ar-alkyl wherein alkyl portion            has 1 to 8 carbon atoms, Het-alkyl wherein alkyl portion has            1 to 8 carbon atoms, aroyl having 7 to 15 carbon atoms            (e.g., benzoyl) in which the aryl portion can be substituted            by halogen, C₁₋₈-alkyl, C₁₋₈-alkoxy, nitro, carboxy,            hydroxyl, phenoxy, benzyloxy or combinations thereof,            -   wherein said phenyl or pyridyl and/or the fused 5 to 7                membered heterocyclic ring is optionally further                substituted by one or more substituents selected from                halogen, alkyl having 1 to 4 carbon atoms, alkoxy having                1 to 4 carbon atoms, NR¹R², nitro, hydroxyl, and cyano,                and            -   wherein said 5 to 7 membered heterocyclic ring is                optionally fused with another aryl group or heteroaryl                group which in each case contains 5 to 10 ring atoms and                in which the heteroaryl group contains 1 to 3 hetero                atoms each selected from O, S, and N, and wherein said                aryl group or heteroaryl group is optionally substituted                one or more times by alkyl having 1 to 8 carbon atoms,                halogenated alkyl having 1 to 8 carbon atoms,                hydroxyalkyl having 1 to 8 carbon atoms, alkenyl having                2 to 8 carbon atoms, alkynyl having 2 to 8 carbon atoms,                alkoxy having 1 to 8 carbon atoms, halogenated alkoxy                having 1 to 8 carbon atoms, cycloalkyl having 3 to 10                carbon atoms (e.g., 3 to 8 carbon atoms),                cycloalkylalkyl having 4 to 14 carbon atoms (e.g., 4 to                8 carbon atoms), Ar-alkyl wherein alkyl portion has 1 to                8 carbon atoms, Het-alkyl wherein alkyl portion has 1 to                8 carbon atoms, COR⁵, COOR⁵, CONR⁵R⁶, halogen, carboxy,                cyano, hydroxyl, NR¹R², nitro, oxo, thio, Ar, Het or                combinations thereof, or        -   (c) thienyl, pyrrolyl, dithienyl, pyrazolyl, imidazolyl,            oxazolyl, isoxazolyl, triazolyl, thiazolyl, or isothiazolyl,            each of which is unsubstituted or substituted one or more            times by alkyl having 1 to 8 carbon atoms, halogenated alkyl            having 1 to 8 carbon atoms, hydroxyalkyl having 1 to 8            carbon atoms, alkenyl having 2 to 8 carbon atoms, alkynyl            having 2 to 8 carbon atoms, alkoxy having 1 to 8 carbon            atoms, halogenated alkoxy having 1 to 8 carbon atoms,            cycloalkyl having 3 to 10 carbon atoms (e.g., 3 to 8 carbon            atoms), cycloalkylalkyl having 4 to 14 carbon atoms (e.g., 4            to 8 carbon atoms), Ar-alkyl wherein alkyl portion has 1 to            8 carbon atoms, Het-alkyl wherein alkyl portion has 1 to 8            carbon atoms, COR⁵, COOR⁵, CONR⁵R⁶, halogen, carboxy, cyano,            hydroxyl, NR¹R², nitro, oxo, thio, Ar, Het or combinations            thereof            -   wherein said thienyl, pyrrolyl, dithienyl, pyrazolyl,                imidazolyl, oxazolyl, isoxazolyl, triazolyl, thiazolyl,                or isothiazolyl group is optionally fused with another                aryl group or heteroaryl group which in each case                contains 5 to 10 ring atoms and in which the heteroaryl                group contains 1 to 3 hetero atoms each selected from O,                S, and N, and wherein said aryl group or heteroaryl                group is optionally substituted one or more times by                alkyl having 1 to 8 carbon atoms, halogenated alkyl                having 1 to 8 carbon atoms, hydroxyalkyl having 1 to 8                carbon atoms, alkenyl having 2 to 8 carbon atoms,                alkynyl having 2 to 8 carbon atoms, alkoxy having 1 to 8                carbon atoms, halogenated alkoxy having 1 to 8 carbon                atoms, cycloalkyl having 3 to 10 carbon atoms (e.g., 3                to 8 carbon atoms), cycloalkalkyl having 4 to 14 carbon                atoms (e.g., 4 to 8 carbon atoms), Ar-alkyl wherein                alkyl portion has 1 to 8 carbon atoms, Het-alkyl wherein                alkyl portion has 1 to 8 carbon atoms, COR⁵, COOR⁵,                CONR⁵R⁶, halogen, carboxy, cyano, hydroxyl, NR¹R²,                nitro, oxo, thio, Ar, Het or combinations thereof;    -   R¹ and R² are each independently H, alkyl having 1 to 8 carbon        atoms or aryl having 6 to 14 (e.g., 6 to 10) carbon atoms;    -   R³ and R⁴ are each independently H, alkyl having 1 to 8 carbon        atoms, halogenated alkyl having 1 to 8 carbon atoms, alkenyl        having 2 to 8 carbon atoms, alkynyl having 2 to 8 carbon atoms,        alkoxy having 1 to 8 carbon atoms, halogenated alkoxy having 1        to 8 carbon atoms, or halogen;    -   R⁵ and R⁶ are each independently H, alkyl having 1 to 8 carbon        atoms, halogenated alkyl having 1 to 8 carbon atoms, alkenyl        having 2 to 8 carbon atoms, alkynyl having 2 to 8 carbon atoms,        cycloalkyl having 3 to 10 carbon atoms (e.g., 3 to 8 carbon        atoms), cycloalkylalkyl having 4 to 14 carbon atoms (e.g., 4 to        8 carbon atoms), Ar, Het, Ar-alkyl wherein alkyl portion has 1        to 8 carbon atoms, Het-alkyl wherein alkyl portion has 1 to 8        carbon atoms;    -   Ar is an aryl group containing 6 to 14 carbon atoms which is        unsubstituted or substituted one or more times by alkyl having 1        to 8 C atoms, alkoxy having 1 to 8 C atoms, halogen (F, Cl, Br,        or I, preferably F or Cl), dialkylamino wherein the alkyl        portions each have 1 to 8 C atoms, amino, cyano, hydroxyl,        nitro, halogenated alkyl having 1 to 8 C atoms, halogenated        alkoxy having 1 to 8 C atoms, hydroxyalkyl having 1 to 8 C        atoms, hydroxyalkoxy having 2 to 8 C atoms, alkenyloxy having 3        to 8 C atoms, alkylthio having 1 to 8 C atoms, alkylsulphinyl        having 1 to 8 C atoms, alkylsulphonyl having 1 to 8 C atoms,        monoalkylamino having 1 to 8 C atoms, cycloalkylamino wherein        the cycloalkyl group has 3 to 10 C atoms and is optionally        substituted, aryl having 6 to 10 carbon atoms, aryloxy wherein        the aryl portion contains 6 to 14 carbon atoms (e.g., phenyl,        naphthyl, biphenyl) and is optionally substituted, arylthio        wherein the aryl portion contains 6 to 14 carbon atoms (e.g.,        phenyl, naphthyl, biphenyl) and is optionally substituted,        cycloalkyloxy wherein the cycloalkyl group has 3 to 10 C atoms        and is optionally substituted, sulfo, sulfonylamino, acylamido        (e.g., acetamido), acyloxy (e.g., acetoxy) or combinations        thereof; and    -   Het is a heterocyclic group, which is fully saturated, partially        saturated or fully unsaturated, having 5 to 14 ring atoms in        which at least 1 ring atom is a N, Q or S atom, which is        substituted one or more times by halogen (F, Cl, Br, or I,        preferably F or Cl), aryl having 6 to 14 carbon atoms (e.g.,        phenyl, naphthyl, biphenyl) and is optionally substituted, e.g.,        alkyl having 1 to 8 C atoms, alkoxy having 1 to 8 C atoms,        cyano, trifluoromethyl, nitro, oxo, amino, monoalkylamino having        1 to 8 C atoms, dialkylamino wherein each alkyl group has 1 to 8        C atoms, or combinations thereof; and    -   pharmaceutically acceptable salts thereof.

The present invention also includes compounds of Formula I′:

wherein

-   -   A is        -   (a) phenyl or pyridyl, each of which is substituted by a 5            to 7 membered heterocyclic ring containing an O, S, Or N            ring atom, and optionally containing a further N ring atom,            wherein the heterocyclic ring is fully unsaturated,            partially saturated or fully saturated and is unsubstituted            or substituted one or more times by alkyl having 1 to 8            carbon atoms, halogenated alkyl having 1 to 8 carbon atoms,            hydroxyalkyl having 1 to 8 carbon atoms, alkenyl having 2 to            8 carbon atoms, alkynyl having 2 to 8 carbon atoms, alkoxy            having 1 to 8 carbon atoms, halogenated alkoxy having 1 to 8            carbon atoms, halogen, carboxy, cyano, hydroxyl, NR¹R²,            nitro, oxo, thio, Ar, Het or combinations thereof,            -   wherein said phenyl or pyridyl is optionally further                substituted by one or more substituents selected from                halogen, alkyl having 1 to 4 carbon atoms, alkoxy having                1 to 4 carbon atoms, NR¹R², nitro, hydroxyl, and cyano,                and            -   wherein said 5 to 7 membered heterocyclic ring is                optionally fused with an aryl group or heteroaryl group                containing 5 to 10 ring atoms in which the heteroaryl                group contains 1 to 3 hetero atoms each selected from O,                S, and N, and wherein said aryl group or heteroaryl                group is optionally substituted one or more times by                alkyl having 1 to 8 carbon atoms, halogenated alkyl                having 1 to 8 carbon atoms, hydroxyalkyl having 1 to 8                carbon atoms, alkenyl having 2 to 8 carbon atoms,                alkynyl having 2 to 8 carbon atoms, alkoxy having 1 to 8                carbon atoms, halogenated alkoxy having 1 to 8 carbon                atoms, halogen, carboxy, cyano, hydroxyl, NR¹R², nitro,                oxo, thio, Ar, Het and combinations thereof,        -   (b) phenyl or pyridyl which in each case is fused with a 5            to 7 membered heterocyclic ring containing 1 to 3 hetero            atoms each selected from O, S, and N, to form a bicyclic            group wherein the fused heterocyclic ring is fully            unsaturated, partially saturated or fully saturated, and            wherein said bicyclic group is unsubstituted or substituted            one or more times by alkyl having 1 to 8 carbon atoms,            halogenated alkyl having 1 to 8 carbon atoms, hydroxyalkyl            having 1 to 8 carbon atoms, alkenyl having 2 to 8 carbon            atoms, alkynyl having 2 to 8 carbon atoms, alkoxy having 1            to 8 carbon atoms, halogenated alkoxy having 1 to 8 carbon            atoms, halogen, carboxy, cyano, hydroxyl, NR¹R², nitro, oxo,            thio, alkylthio (e.g., —S—CH₃), alkylsulfinyl (e.g.,            —SO—CH₃), alkylsulfonyl (e.g., —SO₂—CH₃), aryl having 6 to            10 carbon atoms, arylalkyl having 7 to 14 carbon atoms,            aroyl having 7 to 15 carbon atoms (e.g., benzoyl) in which            the aryl portion can be substituted by halogen, C₁₋₈-alkyl,            C₁₋₈-alkoxy, nitro, carboxy, hydroxyl, phenoxy, benzyloxy or            combinations thereof,            -   wherein said phenyl or pyridyl and/or the fused 5 to 7                membered heterocyclic ring is optionally further                substituted by one or more substituents selected from                halogen, alkyl having 1 to 4 carbon atoms, alkoxy having                1 to 4 carbon atoms, NR¹R², nitro, hydroxyl, and cyano,                and            -   wherein said 5 to 7 membered heterocyclic ring is                optionally fused with another aryl group or heteroaryl                group containing 5 to 10 ring atoms in which the                heteroaryl group contains 1 to 3 hetero atoms each                selected from O, S, and N, and wherein said aryl group                or heteroaryl group is optionally substituted one or                more times by alkyl having 1 to 8 carbon atoms,                halogenated alkyl having 1 to 8 carbon atoms,                hydroxyalkyl having 1 to 8 carbon atoms, alkenyl having                2 to 8 carbon atoms, alkynyl having 2 to 8 carbon atoms,                alkoxy having 1 to 8 carbon atoms, halogenated alkoxy                having 1 to 8 carbon atoms, halogen, carboxy, cyano,                hydroxyl, NR¹R², nitro, oxo, thio, Ar, Het or                combinations thereof, or        -   (c) thienyl, pyrrolyl, dithienyl, pyrazolyl, imidazolyl,            oxazolyl, isoxazolyl, triazolyl, thiazolyl, or isothiazolyl,            each of which is unsubstituted or substituted one or more            times by alkyl having 1 to 8 carbon atoms, halogenated alkyl            having 1 to 8 carbon atoms, hydroxyalkyl having 1 to 8            carbon atoms, alkenyl having 2 to 8 carbon atoms, alkynyl            having 2 to 8 carbon atoms, alkoxy having 1 to 8 carbon            atoms, halogenated alkoxy having 1 to 8 carbon atoms,            halogen, carboxy, cyano, hydroxyl, NR¹R², nitro, oxo, thio,            Ar, Het or combinations thereof,            -   wherein said thienyl, pyrrolyl, dithienyl, pyrazolyl,                imidazolyl, oxazolyl, isoxazolyl, triazolyl, thiazolyl,                or isothiazolyl group is optionally fused with another                aryl group or heteroaryl group containing 5 to 10 ring                atoms in which the heteroaryl group contains 1 to 3                hetero atoms each selected from O, S, and N, and wherein                said aryl group or heteroaryl group is optionally                substituted one or more times by alkyl having 1 to 8                carbon atoms, halogenated alkyl having 1 to 8 carbon                atoms, hydroxyalkyl having 1 to 8 carbon atoms, alkenyl                having 2 to 8 carbon atoms, alkynyl having 2 to 8 carbon                atoms, alkoxy having 1 to 8 carbon atoms, halogenated                alkoxy having 1 to 8 carbon atoms, halogen, carboxy,                cyano, hydroxyl, NR¹R², nitro, oxo, thio, Ar, Het or                combinations thereof;    -   R¹ and R² are each independently H, alkyl having 1 to 8 carbon        atoms or aryl having 6 to 10 carbon atoms;    -   Ar is an aryl group containing 6 to 14 carbon atoms which is        unsubstituted or substituted one or more times by alkyl having 1        to 8 C atoms, alkoxy having 1 to 8 C atoms, halogen (F, Cl, Br,        or L preferably F or Cl), dialkylamino wherein the alkyl        portions each have 1 to 8 C atoms, amino, cyano, hydroxyl,        nitro, halogenated alkyl having 1 to 8 C atoms, halogenated        alkoxy having 1 to 8 C atoms, hydroxyalkyl having 1 to 8 C        atoms, hydroxyalkoxy having 2 to 8 C atoms, alkenyloxy having 3        to 8 C atoms, alkylthio having 1 to 8 C atoms, alkylsulphinyl        having 1 to 8 C atoms, alkylsulphonyl having 1 to 8 C atoms,        monoalkylamino having 1 to 8 C atoms, cycloalkylamino wherein        the cycloalkyl group has 3 to 10 C atoms and is optionally        substituted, aryloxy wherein the aryl portion contains 6 to 14        carbon atoms (e.g., phenyl, naphthyl, biphenyl) and is        optionally substituted, arylthio wherein the aryl portion        contains 6 to 14 carbon atoms (e.g., phenyl, naphthyl, biphenyl)        and is optionally substituted, cycloalkyloxy wherein the        cycloalkyl group has 3 to 10 C atoms and is optionally        substituted, sulfo, sulfonylamino, acylamido (e.g., acetamido),        acyloxy (e.g., acetoxy) or combinations thereof; and    -   Het is a heterocyclic group, which is fully saturated, partially        saturated or fully unsaturated, having 5 to 14 ring atoms in        which at least 1 ring atom is a N, O or S atom, which is        substituted one or more times by halogen (F, Cl, Br, or I,        preferably F or Cl), aryl having 6 to 14 carbon atoms (e.g.,        phenyl, naphthyl, biphenyl) and is optionally substituted, e.g.,        alkyl having 1 to 8 C atoms, alkoxy having 1 to 8 C atoms,        cyano, trifluoromethyl, nitro, oxo, amino, monoalkylamino having        1 to 8 C atoms, dialkylamino wherein each alkyl group has 1 to 8        C atoms, or combinations thereof; and    -   pharmaceutically acceptable salts thereof.

In accordance with a method aspect of the invention, there is provided amethod of treating a patient (e.g., a mammal such as a human) sufferingfrom a disease state (e.g., memory impairment) comprising administeringto the patient a compound according to Formula I or Formula I′.Preferably, the disease state involves decreased nicotinic acetylcholinereceptor activity.

In accordance with a method aspect of the invention there is provided amethod for the treatment or prophylaxis of a disease or conditionresulting from dysfunction of nicotinic acetylcholine receptortransmission in a mammal, e.g. a human, comprising administering aneffective amount of a compound according to Formula I or Formula I′.

In accordance with a method aspect of the invention there is provided amethod for the treatment or prophylaxis of a disease or conditionresulting from defective or malfunctioning nicotinic acetylcholinereceptors, particularly α7nACh receptors, in a mammal; e.g. a human,comprising administering an effective amount of a compound according toFormula I or Formula I′.

In accordance with a method aspect of the invention there is provided amethod for the treatment or prophylaxis of a disease or conditionresulting from suppressed nicotinic acetylcholine receptor transmissionin a mammal, e.g., a human, comprising administering an amount of acompound according to Formula I or Formula I′ effective to activateα7nACh receptors.

In accordance with another method aspect of the invention there isprovided a method for the treatment or prophylaxis of a psychoticdisorder, a cognition impairment (e.g., memory impairment), orneurodegenerative disease in a mammal, e.g., a human, comprisingadministering an effective amount of a compound according to Formula Ior Formula I′.

In accordance with another method aspect of the invention there isprovided a method for the treatment or prophylaxis of a disease orcondition resulting from loss of cholinergic synapse in a mammal, e.g.,a human, comprising administering an effective amount of a compoundaccording to Formula I or Formula I′.

In accordance with another method aspect of the invention there isprovided a method for the treatment or prophylaxis of aneurodegenerative disorder by activation of α7nACh receptors in amammal, e.g., a human, comprising administering an effective amount of acompound according to Formula I or Formula I′.

In accordance with another method aspect of the invention there isprovided a method for protecting neurons in a mammal, e.g., a human,from neurotoxicity induced by activation of α7nACh receptors comprisingadministering an effective amount of a compound according to Formula Ior Formula I′.

In accordance with another method aspect of the invention there isprovided a method for the treatment or prophylaxis of aneurodegenerative disorder by inhibiting the binding of Aβ peptides toα7nACh receptors in a mammal, e.g., a human, comprising administering aneffective amount of a compound according to Formula I or Formula I′.

In accordance with another method aspect of the invention there isprovided a method for protecting neurons in a mammal, e.g., a human,from neurotoxicity induced by Aβ peptides comprising administering aneffective amount of a compound according to Formula I or Formula I′.

In accordance with another method aspect of the invention there isprovided a method for alleviating inhibition of cholinergic functioninduced by Aβ peptides in a mammal, e.g., a human, from neurotoxicitycomprising administering an effective amount of a compound according toFormula I or Formula I′.

The compounds of the present invention are nicotinic alpha-7 ligands,preferably agonists, especially partial agonists, for the alpha-7nicotinic acetylcholine receptor. Assays for determining nicotinicacetylcholine activity are known within the art. See, e.g., Davies, A.R., et al., Characterisation of the binding of [3H]methyllycaconitine: anew radioligand for labelling alpha 7-type neuronal nicotinicacetylcholine receptors. Neuropharmacology, 1999. 38(5): p. 679-90. Asagonists for α-7 nAChRs, the compounds are useful in the prophylaxis andtreatment of a variety of diseases and conditions associated with thecentral nervous system. Nicotinic acetylcholine receptors areligand-gated ion-channel receptors that are composed of five subunitproteins which form a central ion-conducting pore. Presently, there areeleven known neuronal nAChR subunits (α2-α9 and β2-β4). There are alsofive further subunits expressed in the peripheral nervous system (α1,β1, γ, δ, ε).

The nAChR receptor subtypes can be homopentameric or heteropentameric.The subtype which has received considerable attention is thehomopentameric α7 receptor subtype formed from five α7 subunits. Theα7nAChRs exhibit a high affinity for nicotine (agonist) and forα-bungarotoxin (antagonist). Studies have shown the α7-nAChR agonistscan be useful in the treatment of psychotic diseases, neurodegenerativediseases, and cognitive impairments, among other things. While nicotineis a known agonist, there is a need for the development of otherα7-nAChR agonists, especially selective agonists, that are less toxic orexhibit fewer side effects than nicotine.

The compound anabaseine, i.e., 2-(3-pyridyl)-3,4,5,6-tetrahydropyridineis a naturally occurring toxin in certain marine worms (nemertine worms)and ants. See, e.g., Kem et al., Toxicon, 9:23, 1971. Anabaseine is apotent activator of mammalian nicotinic receptors. See, e.g., Kem, Amer.Zoologist, 25, 99, 1985. Certain anabaseine analogs such as anabasineand DMAB(3-[4-(dimethylamino)benzylidene]-3,4,5,6-tetrahydro-2′,3′-bipyridine)are also known nicotinic receptor agonists. See, e.g., U.S. Pat. No.5,602,257 and WO 92/15306. One particular anabaseine analog,(E-3-[2,4-dimethoxy-benzylidene]-anabaseine, also known as GTS-21 andDMXB (see, e.g., U.S. Pat. No. 5,741,802), is a selective partialα7-nAChR agonist that has been studied extensively. For example,abnormal sensory inhibition is a sensory processing deficit inschizophrenics and GTS-21 has been found to increase sensory inhibitionthrough interaction with α7-nAChR s. See, e.g., Stevens et al.,Psychopharmacology, 136: 320-27 (1998).

With regards to the compounds of Formula I and Formula I′, halogenherein refers to F, Cl, Br, and I. Preferred halogens are F and Cl.

Alkyl throughout means a straight-chain or branched-chain aliphatichydrocarbon radical having preferably 1 to 8 carbon atoms, especially 1to 4 carbon atoms. Suitable alkyl groups include methyl, ethyl, propyl,isopropyl, butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, andoctyl. Other examples of suitable alkyl groups include 1-, 2- or3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, 1-, 2-,3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl,1- or 2-ethylbutyl, ethylmethylpropyl, trimethylpropyl, methylhexyl,dimethylpentyl, ethylpentyl, ethylmethylbutyl, dimethylbutyl, and thelike.

Suitable alkenyl or alkynyl groups are 1-propenyl, 2-propenyl(allyl),1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, ethynyl,1-propynyl, 2-propynyl, 1-butynyl, 1,3-butadienyl and3-methyl-2-butenyl.

Alkoxy means alkyl-O— groups in which the alkyl portion preferably has 1to 8, more preferably 1 to 6 carbon atoms, especially 1 to 4 carbonatoms. Suitable alkoxy groups include methoxy, ethoxy, propoxy,isopropoxy, isobutoxy, sec-butoxy, pentoxy, hexoxy, heptoxy, and octoxy.Preferred alkoxy groups are methoxy and ethoxy. Similarly,alkoxycarbonyl means an alkyl-O—CO— group in which the alkyl portion has1 to 8 carbon atoms.

Cycloalkyl means a monocyclic, bicyclic or tricyclic saturatedhydrocarbon radical having 3 to 10 carbon atoms, preferably 3 to 8carbon atoms, especially 3 to 6 carbon atoms. Suitable cycloalkyl groupsinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, and norbornyl. Other suitable cycloalkyl groups includespiropentyl, bicyclo[2.1.0]pentyl, bicyclo[3.1.0]hexyl,spiro[2.4]heptyl, spiro[2.5]octyl, bicyclo[5.1.0]octyl, spiro[2.6]nonyl,bicyclo[2.2.0]hexyl, spiro[3.3]heptyl, and bicyclo[4.2.0]octyl.Preferred cycloalkyl groups are cyclopropyl, cyclopentyl, andcyclohexyl.

The cycloalkyl group can be substituted by C₁₋₄-alkyl, C₁₋₄-alkoxy,hydroxyl, amino, monoalkylamino having 1 to 4 C atoms, and/ordialklyamino in which each alkyl group has 1 to 4 C atoms.

Cycloalkylalkyl groups contain 4 to 14 carbon atoms, for example,cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl,cyclopentylmethyl, and cyclohexylmethyl.

Aryl, as a group or substituent per se or as part of a group orsubstituent, refers to an aromatic carbocyclic radical containing 6 to14 carbon atoms, preferably 6 to 10 carbon atoms, unless indicatedotherwise. Suitable aryl groups include phenyl, napthyl and biphenyl.Substituted aryl groups include the above-described aryl groups whichare substituted one or more times by halogen, alkyl, hydroxy, alkoxy,nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino,hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl,alkylthio, alkylsulphinyl, alkylsulphonyl, phenoxy, and acyloxy (e.g.,acetoxy).

Heterocyclic groups refer to saturated, partially saturated andunsaturated heterocyclic groups having one, two or three rings and atotal number of 5 to 14, preferably 5 to 10, ring atoms wherein at leastone of the ring atoms is an N, O or S atom. Preferably, the heterocyclicgroup contains 1 to 3 hetero-ring atoms selected from N, O and S.Suitable saturated and partially saturated heterocyclic groups include,but are not limited to tetrahydrofuranyl, tetrahydrothienyl,pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, isoxazolinyl andthe like. Suitable heteroaryl groups include but are not limited tofuryl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl,indolyl, quinolinyl, naphthyridinyl and the like. Preferred heterocyclicand heteroaryl groups include tetrahydrofuranyl, tetrahydropyranyl,2-thienyl, 3-thienyl, 2-, 3- or 4-pyridyl, 2-, 3-, 4-, 5-, 6-, 7- or8-quinolinyl, and 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolinyl. Otherexamples of suitable heterocyclic groups, are 2-quinolinyl,1,3-benzodioxyl, 2-thienyl, 2-benzofuranyl, 2-benzothiofuranyl,3-thienyl, 2,3-dihydro-5-benzofuranyl, 4-indoyl, 4-pyridyl,3-qionolinyl, 4-quinolinyl, 1,4-benzodioxan-6-yl, 3-indoyl, 2-pyrrolyl,3,4-1,2-benzopyran-6-yl, 5-indolyl, 1,5-benzoxepin-8-yl, 3-pyridyl,6-coumarinyl, 5-benzofuranyl, 2-isoimidazol-4-yl, 3-pyrazolyl, and3-carbazolyl.

Substituted heterocyclic groups refer to the heterocyclic groupsdescribed above which are substituted in one or more places by, forexample, halogen, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro,oxo, amino, alkylamino, and dialkylamino.

Acyl refers to alkanoyl radicals having 1 to 13 carbon atoms in whichthe alkyl portion can be substituted by halogen, hydroxy, carboxy,amino, thio, C₁₋₈-alkyl, aryl having 6 to 14 C atoms and/or C₁₋₈-alkoxy,or aroyl radicals having 7 to 15 carbon atoms in which the aryl portioncan be substituted by halogen, C₁₋₈-alkyl, C₁₋₈-alkoxy, nitro, carboxyand/or hydroxy. Suitable acyl groups include formyl, acetyl, propionyl,butanoyl and benzoyl.

Radicals which are substituted one or more times preferably have 1 to 3substituents, especially 1 or 2 substituents of the exemplifiedsubstituents. Halogenated radicals such as halogenated alkyls includeperhalo radicals such as trifluoromethyl.

In the compounds of Formula I or Formula I′, A is preferably pyrrolyl,thienyl, benzofuranyl, benzothiophenyl (benzothienyl), pyrazolyl,indazolyl, phenyl or indolyl which in each case is unsubstituted or issubstituted by allyl having 1 to 8 C atoms, alkoxy having 1 to 8 Catoms, halogen, carboxy, oxo, nitro, oxide, alkoxycarbonyl having 2 to 8C atoms, alkyl-sulfonyl having 1 to 8 C atoms, Ar, Ar—CO—, Ar-sulfonyl,Ar—O—, Ar-alkyl-O— wherein the alkylene group has 1 to 8 C atoms,Ar-thio, Hetero, cyano, trifluoromethyl, halogenated-alkyl having 1 to 8C atoms, halogenated-alkoxy having 1 to 8 C atoms, amino, monoalkylaminohaving 1 to 8 C atoms, dialkylamino wherein each alkyl group has 1 to 8C atoms, hydroxyl, hydroxyalkyl having 1 to 8 C atoms, hydroxyalkoxyhaving 2 to 8 C atoms, acyl, alkylthio having 1 to 8 C atoms,alkylsulphinyl having 1 to 8 C atoms, acylamido (e.g., acetamido), andacyloxy (e.g., acetoxy).

R³ and R⁴ are each preferably H.

In addition, in accordance with the invention, preferred compounds arethose described by subformulas Ia-Ip, which correspond to Formula I, butexhibit the following preferred groups:

-   -   Ia A is dihydrobenzofuranyl, e.g., 2,3-dihydrobenzofuran-5-yl,        which is unsubstituted or substituted by alkyl, alkoxy, halogen,        carboxy, oxo, nitro, alkoxycarbonyl, cyano, trifluoromethyl,        amino, monoalkylamino, dialkylamino, hydroxyl, hydroxyalkyl, or        combinations thereof.    -   Ib A is dihydrobenzodioxinyl, e.g.,        2,3-dihydrobenzo[1,4]dioxin-6-yl, which is unsubstituted or        substituted by alkyl, alkoxy, halogen, carboxy, oxo, nitro,        alkoxycarbonyl, cyano, trifluoromethyl, amino, monoalkylamino,        dialkylamino, hydroxyl, hydroxyalkyl, or combinations thereof.    -   Ic A is chromanyl, e.g., chroman-6-yl, which is substituted or        substituted by alkyl, alkoxy, halogen, carboxy, oxo, nitro,        alkoxycarbonyl, cyano, trifluoromethyl, amino, monoalkylamino,        dialkylamino, hydroxyl, hydroxyalkyl, or combinations thereof.    -   Id A is dihydrobenzodioxepinyl, e.g.,        3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl, which is        unsubstituted or substituted by alkyl, alkoxy, halogen, carboxy,        oxo, nitro, alkoxycarbonyl, cyano, trifluoromethyl, amino,        monoalkylamino, dialkylamino, hydroxyl, hydroxyalkyl, or        combinations thereof.    -   Ie A is indolyl, e.g., indol-3-yl, indol-4-yl, indol-5-yl,        indol-6-yl, which is unsubstituted or substituted by alkyl,        alkoxy, halogen, carboxy, oxo, nitro, alkoxycarbonyl, cyano,        trifluoromethyl, amino, monoalkylamino, dialkylamino, hydroxyl,        hydroxyalkyl, or combinations thereof.    -   If A is phenyl substituted by a heterocylic group (e.g.,        4-(4-morpholinyl)-phenyl, 4-(pyrrolidin-1-yl)-phenyl,        4-(piperidin-1-yl)-phenyl, 3-(piperidin-1-yl)-phenyl,        4-(piperazin-1-yl)-phenyl, 4-(thiomorpholin-4-yl)-phenyl,        4-(1,4-diazepan-1-yl)-phenyl, 4-(1,4-oxazepan-4-yl)-phenyl),        which is unsubstituted or substituted by alkyl, alkoxy,        cyloalkyl, cycloalkylalkyl, halogen, carboxy, oxo, nitro,        alkoxycarbonyl, cyano, trifluoromethyl, amino, monoalkylamino,        dialkylamino, hydroxyl, hydroxyalkyl, —COR⁵, or combinations        thereof.    -   Ig A is benzoxazinyl, e.g.,        3,4-dihydro-2H-benzo[1,4]oxazin-7-yl, which is unsubstituted or        substituted by alkyl, alkoxy, cycloalkyl, cycloalkylalkyl,        halogen, carboxy, oxo, nitro, alkoxycarbonyl, cyano,        trifluoromethyl, amino, monoalkylamino, dialkylamino, hydroxyl,        or hydroxyalkyl, or combinations thereof.    -   Ih A is indazolyl, e.g., indazol-3-yl, indazol-4-yl,        indazol-5-yl, indazol-6-yl, which is unsubstituted or        substituted by alkyl, alkoxy, halogen, carboxy, oxo, nitro,        alkoxycarbonyl, cyano, trifluoromethyl, amino, monoalkylamino,        dialkylamino, hydroxyl, hydroxyalkyl, or combinations thereof.    -   Ii A is benzoimidazolyl, e.g., benzoimidazol-5-yl, which is        unsubstituted or substituted by alkyl, alkoxy, halogen, carboxy,        oxo, nitro, alkoxycarbonyl, cyano, trifluoromethyl, amino,        monoalkylamino, dialkylamino, hydroxyl, hydroxyalkyl, or        combinations thereof.    -   Ij A is phenylpiperazinyl, e.g., 4-phenylpiperazin-1-yl, which        is unsubstituted or substituted by alkyl, alkoxy, cycloalkyl,        cycloalkylalkyl, halogen, carboxy, oxo, nitro, alkoxycarbonyl,        cyano, trifluoromethyl, amino, monoalkylamino, dialkylamino,        hydroxyl, hydroxyalkyl, Ar or combinations thereof.    -   Ik A is benzothiazolyl (e.g., benzothiazol-5-yl,        benzothiazol-6-yl) which is unsubstituted or substituted by        alkyl, alkoxy, cycloalkyl, cycloalkylalkyl, halogen, carboxy,        oxo, nitro, alkoxycarbonyl, cyano, trifluoremethyl, amino,        monoalkylamino, dialkylamino, hydroxyl, hydroxyalkyl, or        combinations thereof.    -   Il A is pyrrolyl (e.g., 1H-pyrrol-2-yl) which is unsubstituted        or substituted by alkyl, alkoxy, cycloalkyl, cycloalkylalkyl,        halogen, carboxy, oxo, nitro, alkoxycarbonyl, cyano,        trifluoromethyl, amino, monoalkylamino, dialkylamino, hydroxyl,        hydroxyalkyl, aryl (e.g. phenyl) which is unsubstituted or        substituted by halogen, halogenated alkyl, or halogenated        alkoxy, or arylalkyl (benzyl, biphenylmethyl) which is        unsubstituted or substituted by halogen, halogenated alkyl, or        halogenated alkoxy, or combinations thereof.    -   Im A is pyrazolyl (e.g., 2H-pyrazol-3-yl) which is unsubstituted        or substituted by alkyl, alkoxy, cycloalkyl, cycloalkylalkyl,        halogen, carboxy, oxo, nitro, alkoxycarbonyl, cyano,        trifluoromethyl, amino, monoalkylamino, dialkylamino, hydroxyl,        hydroxyalkyl, Ar (e.g. phenyl) which is unsubstituted or        substituted by halogen, halogenated alkyl, or halogenated        alkoxy, or arylalkyl (benzyl, biphenylmethyl) which is        unsubstituted or substituted by halogen, halogenated alkyl, or        halogenated alkoxy, or combinations thereof.    -   In A is diazabicycloheptyl (e.g.,        2,5-diazabicyclo[2.2.1]hept-2-yl) which is unsubstituted or        substituted by alkyl, alkoxy, cycloalkyl, cycloalkylalkyl,        halogen, carboxy, oxo, nitro, alkoxycarbonyl, cyano,        trifluoromethyl, amino, monoalkylamino, dialkylamino, hydroxyl,        hydroxyalkyl, or combinations thereof.    -   Io A is benzodioxolyl (e.g., benzo[1,3]dioxol-5-yl) which is        unsubstituted or substituted by alkyl, alkoxy, cycloalkyl,        cycloalkylalkyl, halogen, carboxy, oxo, nitro, alkoxycarbonyl,        cyano, trifluoromethyl, amino, monoalkylamino, dialkylamino,        hydroxyl, hydroxyalkyl, or combinations thereof.    -   Ip A is dihydrobenzodioinyl (e.g.,        2,3-dihydrobenzo[1,4]dioin-6-yl) which is unsubstituted or        substituted by alkyl, alkoxy, cycloalkyl, cycloalkylalkyl,        halogen, carboxy, oxo, nitro, alkoxycarbonyl, cyano,        trifluoromethyl, amino, monoalkylamino, dialkylamino, hydroxyl,        or hydroxyalkyl, or combinations thereof.

According to a further preferred compound aspect of the invention, thecompound of formula I is selected from:

-   3-Quinolin-2-ylmethylene-3,4,5,6-terahydro[2,3′]bipyridinyl;-   3-Quinolin-3-ylmethylene-3,4,5,6-terahydro[2,3′]bipyridinyl;-   3-(3,4-Dihydroquinolin-4-ylmethylene)-3,4,5,6-terahydro[2,3′]bipyridinyl;-   3-[1-(Toluene-4-sulfonyl-1H-indol-4-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(1H-Indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(1H-Indol-4-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(1H-Pyrrol-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl-1H-indole-6-carboxylic    acid Methyl Ester;-   3-(5-Methoxy-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(1H-Indol-5-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(6-Benzyloxy-2H-pyrrolo[3,3-c]pyridin-1-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(1-Methyl-1H-indol-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(1-Methyl-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(4-Benzyloxy-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(2-Methyl-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(3H-Imidazol-4-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(1-Methyl-1H-pyrrol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(5-Fluoro-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(6-Methyl    1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(7-Methyl-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(5-Benzyloxy-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(2-Methyl-5-nitro-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   [5-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)benzofuran-2-yl]phenylmethanone;-   6-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)chromen-2-one;-   3-(5′-Bromo-1H,1′H-[2,2′]bipyrrolyl-5-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl    Dihydrochloride;-   5-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)-1H-thiophene-2-carboxylic    acid Dihydrochloride;-   3-(2,3-Dihydrobenzo[1,4]dioxin-6-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl    Dihydrochloride;-   3-[5-(4-Bromophenyl)-thiophen-2-ylmethylene]-3,4,5,6-tetrahydro-[2,3′]bipyridinyl    Dihydrochloride;-   3-[1-(Toluene-4-sulfonyl-1H-indol-3-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl    Dihydrochloride;-   3-[1-Methanesulfonyl-1H-indol-3-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl    Dihydrochloride;-   3-(Thiophen-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl    Dihydrochloride;-   3-(Benzofuran-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl    Dihydrochloride;-   3-(5-Propylthiophen-2-ylmethylene)-3,4,5,6-terahydro[2,3′]bipyridinyl    Dihydrochloride;-   3-(5-Bromothiophen-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl    Dihydrochloride;-   3-(5-Methylthiophen-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl    Dihydrochloride;-   3-(4-Bromothiophen-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl    Dihydrochloride;-   4-[5-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)thiophen-2-yl]phenol    Dihydrobromide;-   3-(Benzo[b]thiophen-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl    Dihydrochloride;-   3-(Thiophen-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl    Dihydrochloride;-   3-(Benzo[b]thiophen-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl    Dihydrochloride;-   3-(2,3-Dihydrobenzofuran-5-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl    Dihydrochloride;-   3-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-7-ylmethylene)-3,4,5,6-tetrahydro-[2,3′]bipyridinyl    Dihydrochloride;-   3-(2,2-Dimethylchroman-6-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl    Dihydrochloride;-   3-(2,2-Difluorobenzo[1,3]dioxol-5-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl    Dihydrochloride;-   3-(7-Methoxybenzo[1,3]dioxol-5-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl    Dihydrochloride;-   3-(Benzo[1,3]dioxol-5-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(5-Bromo-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   4-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)-2-nitrophenol;-   3-(1-Methyl-1H-pyrrol-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)cinnoline;-   3-(3-Nitro-4-piperidin-1-ylbenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(4-(Pyrazol-1-yl)benzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   7-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)-4H-benzo[1,4]oxazin-3-one;-   6-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)-4H-benzo[1,4]oxazin-3-one;-   3-(3-Morpholin-4-ylbenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(3-Pyrrolidin-1-ylbenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-[3-(4-Methylpiperazin-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(Benzo[1,3]dioxol-4-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl    Dihydrochloride,-   3-(4-Pyrrolidin-1-yl-benzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl,-   3-[2-(4-Methylpiperazin-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl,-   3-(1H-Indazol-6-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl,-   3-(1H-Indazol-5-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl,-   3-(2-Morpholin-4-ylbenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl,-   3-(1H-Benztriazol-5-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl,-   5-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)-1,3-dihydrobenzimidazol-2-one,-   3-(1H-Benzimidazol-5-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl,-   3-(4-Morpholin-4-yl-benzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl,-   3-[4-(4-Methylpiperazin-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl,-   3-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)-10-methyl-10H-phenothiazine,-   7-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazine,-   3-(1H-Pyrrolo[2,3-b]pyridin-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl,-   3-(6-Methoxy-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl,-   3-(5,6-Dihydro-4H-[2,3′]-bipyridinyl-3-ylidenemethyl)-9-methyl-9H-carbazole,-   3-(4-Methoxy-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl,-   3-(7-Methoxy-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl,-   3-(6-Fluoro-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl,-   3-(1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl    dihydrochloride,-   3-(1H-indol-6-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl,-   3-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)-9-ethyl-9H-carbazole    dihydrochloride,-   3-(1-Benzyl-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl,-   3-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)-9-ethyl-9H-carbazole,-   3-(5-Nitro-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl,-   3-(5-Chloro-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro-[2,3′]bipyridinyl,-   3-(3-Nitro-4-pyrrolidin-1-ylbenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(3-Amino-4-pyrrolidin-1-ylbenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(3-Amino-4-piperidin-1-ylbenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(3-Amino-4-morpholin-4-ylbenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(5-Chloro-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl    dihydrochloride;-   3-(1H-Indazol-4-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(3-Piperidin-1-ylbenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(Benzothiazol-5-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(3,4-Dihydro-2H-benzo[1,4]oxazin-7-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(3,4-Dihydro-2H-benzo[1,4]oxazin-7-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl    trihydrochloride;-   3-(4-Cyclopropylmethyl-3,4-dihydro-2H-benzo[1,4]oxazin-7-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(4-Ethyl-3,4-dihydro-2H-benzo[1,4]oxazin-7-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(Benzothiazol-6-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(1-Phenyl-1H-pyrrol-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-[2-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)pyrrol-1-yl]benzonitrile;-   3-(2-Cyclohexylmethyl-2H-pyrazol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(2-Cyclopentyl-2H-pyrazol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-[1-(4-Chlorophenyl)-1H-pyrrol-2-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-[1-(4-Trifluoromethoxyphenyl)-1H-pyrrol-2-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-[4-(trans-2,5-Dimethylpiperazin-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   [3-[4-(cis-3,5-Dimethylpiperazin-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(4-Thiomorpholin-4-yl-benzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-[4-(1-Oxo-1λ4-thiomorpholin-4-yl)-benzylidene]-3,4,5,6-tetrahydro-[2,3′]bipyridinyl;-   3-[4-(1,1-Dioxo-1λ6-thiomorpholin-4-yl)-benzylidene]-3,4,5,6-tetrahydro-[2,3′]bipyridinyl;-   3-[4-(2,6-Dimethylmorpholin-4-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(4-[1,4]Diazepan-1-ylbenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(4-piperazin-1-ylbenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-[3-(trans-2,5-Dimethylpiperazin-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-[3-(cis-3,5-Dimethylpiperazin-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(3-Thiomorpholin-4-yl-benzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-[3-(2,6-Dimethylmorpholin-4-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(3-[1,4]Diazepan-1-ylbenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-[3-(4-Phenylpiperazin-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-{3-[4-(4-Fluorophenyl)piperazin-1-yl]benzylidene}-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(3-piperazin-1-benzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-{3-[(1S,4S)-2,5-Diazabicyclo[2.2.1]hept-2-yl]benzylidene}-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(3-[1,4]Oxazepan-4-ylbenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-[4-(4-Phenylpiperazin-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-{4-[4-(4-Fluorophenyl)piperazin-1-yl]benzylidene}-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-{4-[(1S,4S)-2,5-Diazabicyclo[2.2.1]hept-2-yl]benzylidene}-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(4-[1,4]Oxazepan-4-ylbenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-[4-(3-Methylpiperazin-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-[4-(2-Methylpiperazin-1-yl)benzylidene]-3-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-[3-(4-Ethylpiperazin-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-[4-(4-Ethylpiperazin-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-[1-(4-Chlorobenzyl)-1H-pyrrol-2-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-[1-(4-Fluorobenzyl)-1H-pyrrol-2-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-[1-(4-Trifluoromethylbenzyl)-1H-pyrrol-2-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-[1-(4-Chlorobenzyl)-1H-pyrazol-3-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-[1-(4-Fluorobenzyl)-1H-pyrazol-3-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-[1-(2,6-Dichlorobenzyl)-1H-pyrrol-2-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-[1-(3,4-Dichlorobenzyl)-1H-pyrrol-2-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-[1-(4-Trifluoromethoxybenzyl)-1H-pyrrol-2-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(1-Biphenyl-4-ylmethyl-1H-pyrrol-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-[1-(2-Fluorobenzyl)-1H-pyrrol-2-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(1-Methylpropyl-1H-pyrrol-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(1-Pyridin-4-ylmethyl-1H-pyrrol-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-[1-(1-Ethylpropyl)-1H-pyrrol-2-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-[1-(2-Chloro-6-fluorobenzyl)-1H-pyrrol-2-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(1-Pentafluorophenylmethyl-1H-pyrrol-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-[1-(2,4,5-Trifluorobenzyl)-1H-pyrrol-2-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(1-Ethyl-1H-pyrazol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-[1-(2-Methylpropyl)-1H-pyrazol-3-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(1-Cyclopropylmethyl-1H-pyrazol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(1-Cyclobutylmethyl-1H-pyrazol-3-ylmethylene)-3,4,5,6-tetrahydro-[2,3′]bipyridinyl;-   3-(1-Cyclohexylmethyl-1H-pyrazol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(1-Cyclopentyl-1H-pyrazol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-[5-Bromo-2-(4-chlorobenzyl)-2H-pyrazol-3-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-[4-(4-Cyclopropylmethylpiperazin-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-[4-(4-Cyclopentylpiperazin-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-{4-[(1S,4S)-5-Methyl-2,5-Diazabicyclo[2.2.1]hept-2-yl]benzylidene}-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-{4-[(1S,4S)-5-Ethyl-2,5-Diazabicyclo[2.2.1]hept-2-yl]benzylidene}-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-{4-[(1S,4S)-5-Cyclopropylmethyl-2,5-Diazabicyclo[2.2.1]hept-2-yl]benzylidene}-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-[4-(4-Methyl[1,4]diazepan-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-[4-(4-Cyclopropylmethyl[1,4]diazepan-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-[4-(4-Cyclopentyl[1,4]diazepan-1-yl)-benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl-   3-[4-(4-Isobutyl-[1,4]diazepan-1-yl)-benzylidene]-3,4,5,6-tetrahydro-[2,3′]bipyridinyl;-   3-{4-[(1S,4S)-5-(2-Methylpropyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]benzylidene}-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-{4-[(1S,4S)-5-Cyclopentyl-2,5-diazabicyclo[2.2.1]hept-2-yl]benzylidene}-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-[4-(4-Ethyl[1,4]diazepan-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   Cyclopropyl-{-[4-(5,6-dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)phenyl]piperazin-1-yl}methanone;-   1-{4-[4-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)phenyl]piperazin-1-yl}propan-1-one;-   1-{4-[4-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)phenyl]piperazin-1-yl}-2,2,2-trifluoroethanone;-   Cyclopropyl-{(1S,4S)-5-[4-(5,6-dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)phenyl]-2,5-diazabicyclo[2.2.1]hept-2-yl}methanone;-   Cyclopropyl-{4-[4-(5,6-dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)phenyl][1,4]diazepan-1-yl}methanone;-   1-{(1S,4S)-5-[4-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)phenyl]-2,5-diazabicyclo[2.2.1]hept-2-yl}-2,2,2-trifluoroethanone;-   1-{(1S,4S)-5-[4-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)phenyl]-2,5-diazabicyclo[2.2.1]hept-2-yl}propan-1-one;-   1-{4-[4-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)phenyl][1,4]diazepan-1-yl}-2,2,2-trifluoroethanone;-   1-{4-[4-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)phenyl][1,4]diazepan-1-yl}propan-1-one;-   Cyclopropyl-{(1S,4S)-5-[3-(5,6-dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)phenyl]-2,5-diazabicyclo[2.2.1]hept-2-yl}methanone;-   1-{(1S,4S)-5-[3-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)phenyl]-2,5-diazabicyclo[2.2.1]hept-2-yl}-2,2,2-trifluoroethanone;-   Cyclopropyl-{4-[3-(5,6-dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)phenyl]-[1,4]diazepan-1-yl}methanone;-   1-{4-[3-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)phenyl][1,4]diazepan-1-yl}-2,2,2-trifluoroethanone;-   1-{4-[3-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)phenyl]-[1,4]diazepan-1-yl}propan-1-one;-   3-(Benzo[1,3]dioxol-5-ylmethylene)-5′-methyl-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(1H-Indol-3-ylmethylene)-5′-methyl-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   5′-Methyl-3-(1H-pyrrol-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(Benzo[1,3]dioxol-5-ylmethylene)-5′-fluoro-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   5′-Fluoro-3-(1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   5′-Fluoro-3-(1H-pyrrol-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(2,3-Dihydrobenzo[1,4]dioxin-6-ylmethylene)-5′-fluoro-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(1-Cyclopropylmethyl-1H-pyrrol-2-ylmethylene)-5′-fluoro-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   5′-Fluoro-3-(4-morpholin-4-ylbenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(H-Indol-3-ylmethylene)-6′-trifluoromethyl-3,4,5,6-tetrahydro[2,3′];    and

physiologically acceptable salts thereof.

Accordingly to a preferred method of use aspect of the invention, thecompound of Formula I is selected from:

-   3-Quinolin-2-ylmethylene-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-Quinolin-3-ylmethylene-3,4,5,6-terahydro[2,3′]bipyridinyl;-   3-(3,4-Dihydroquinolin-4-ylmethylene)-3,4,5,6-terahydro[2,3′]bipyridinyl;-   3-[1-(Toluene-4-sulfonyl-1H-indol-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(1H-Indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(1H-Indol-4-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(1H-Pyrrol-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl-1H-indole-6-carboxylic    acid Methyl Ester;-   3-(5-Methoxy-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(1H-Indol-5-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(6-Benzyloxy-2H-pyrrolo[3,3-c]pyridin    1-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(1-Methyl-1H-indol-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(1-Methyl-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(4-Benzyloxy-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(2-Methyl-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(3H-Imidazol-4-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(1-Methyl-1H-pyrrol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(5-Fluoro-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(6-Methyl-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(7-Methyl-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(5-Benzyloxy-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(2-Methyl-5-nitro-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   [5-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)benzofuran-2-yl]phenylmethanone;-   6-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)chromen-2-one;-   3-(5′-Bromo-1H,1′H-[2,2′]bipyrrolyl-5-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl    Dihydrochloride;-   5-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)-1H-thiophene-2-carboxylic    acid Dihydrochloride;-   3-(2,3-Dihydrobenzo[1,4]dioxin-6-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl    Dihydrochloride;-   3-[5-(4-Bromophenyl)-thiophen-2-ylmethylene]-3,4,5,6-tetrahydro-[2,3′]bipyridinyl    Dihydrochloride;-   3-[1-(Toluene-4-sulfonyl-1H-indol-3-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl    Dihydrochloride;-   3-[1-Methanesulfonyl-1H-indol-3-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl    Dihydrochloride;-   3-(Thiophen-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl    Dihydrochloride;-   3-(Benzofuran-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl    Dihydrochloride;-   3-(5-Propylthiophen-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl    Dihydrochloride;-   3-(5-Bromothiophen-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl    Dihydrochloride;-   3-(5-Methylthiophen-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl    Dihydrochloride;-   3-(4-Bromothiophen-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl    Dihydrochloride;-   4-[5-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)thiophen-2-yl]phenol    Dihydrobromide;-   3-(Benzo[b]thiophen-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl    Dihydrochloride;-   3-(Thiophen-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl    Dihydrochloride;-   3-(Benzo[b]thiophen-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl    Dihydrochloride;-   3-(2,3-Dihydrobenzofuran-5-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl    Dihydrochloride;-   3-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-7-ylmethylene)-3,4,5,6-tetrahydro-[2,3′]bipyridinyl    Dihydrochloride;-   3-(2,2-Dimethylchroman-6-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl    Dihydrochloride;-   3-(2,2-Difluorobenzo[1,3]dioxol-5-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl    Dihydrochloride;-   3-(7-Methoxybenzo[1,3]dioxol-5-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl    Dihydrochloride;-   3-(Benzo[1,3]dioxol-5-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;    3-(5-Bromo-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   4-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)-2-nitrophenol;-   3-(1-Methyl-1H-pyrrol-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)cinnoline;-   3-(3-Nitro-4-piperidin-1-ylbenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(4-(Pyrazol-1-yl)benzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   7-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)-4H-benzo[1,4]oxazin-3-one;-   6-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)-4H-benzo[1,4]oxazin-3-one;-   3-(3-Morpholin-4-ylbenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(3-Pyrrolidin-1-ylbenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-[3-(4-Methylpiperazin-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(Benzo[1,3]dioxol-4-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl    Dihydrochloride,-   3-(4-Pyrrolidin-1-yl-benzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl,-   3-[2-(4-Methylpiperazin-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl,-   3-(1H-Indazol-6-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl,-   3-(1H-Indazol-5-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl,-   3-(2-Morpholin-4-ylbenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl,-   3-(1H-Benztriazol-5-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl,-   5-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)-1,3-dihydrobenzimidazol-2-one,-   3-(1H-Benzimidazol-5-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl,-   3-(4-Morpholin-4-yl-benzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl,-   3-[4-(4-Methylpiperazin    1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl,-   3-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)-10-methyl-10H-phenothiazine,-   7-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazine,-   3-(1H-Pyrrolo[2,3-b]pyridin-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl,-   3-(6-Methoxy-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl,-   3-(5,6-Dihydro-4H-[2,3′]-bipyridinyl-3-ylidenemethyl)-9-methyl-9H-carbazole,-   3-(4-Methoxy-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl,-   3-(7-Methoxy-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl,-   3-(6-Fluoro-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl,-   3-(1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl    dihydrochloride,-   3-(1H-indol-6-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl,-   3-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)-9-ethyl-9H-carbazole    dihydrochloride,-   3-(O-Benzyl-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl,-   3-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)-9-ethyl-9H-carbazole,-   3-(5-Nitro-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl,-   3-(5-Chloro-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro-[2,3′]bipyridinyl,-   3-(3-Nitro-4-pyrrolidin-1-ylbenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(3-Amino-4-pyrrolidin-1-ylbenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(3-Amino-4-piperidin-1-ylbenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(3-Amino-4-morpholin-4-ylbenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(5-Chloro-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl    dihydrochloride;-   3-(1H-Indazol-4-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(3-Piperidin-1-ylbenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(Benzothiazol-5-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(3,4-Dihydro-2H-benzo[1,4]oxazin-7-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(3,4-Dihydro-2H-benzo[1,4]oxazin-7-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl    trihydrochloride;-   3-(4-Cyclopropylmethyl-3,4-dihydro-2H-benzo[1,4]oxazin-7-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(4-Ethyl-3,4-dihydro-2H-benzo[1,4]oxazin-7-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(Benzothiazol-6-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(1-Phenyl-1H-pyrrol-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-[2-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)pyrrol-1-yl]benzonitrile;-   3-(2-Cyclohexylmethyl-2H-pyrazol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(2-Cyclopentyl-2H-pyrazol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-[1-(4-Chlorophenyl)-1H-pyrrol-2-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-[1-(4-Trifluoromethoxyphenyl)-1H-pyrrol-2-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-[4-(trans-2,5-Dimethylpiperazin-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   [3-[4-(cis-3,5-Dimethylpiperazin-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(4-Thiomorpholin-4-yl-benzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-[4-(1-Oxo-1λ4-thiomorpholin-4-yl)-benzylidene]-3,4,5,6-tetrahydro-[2,3′]bipyridinyl;-   3-[4-(1,1-Dioxo-1λ6-thiomorpholin-4-yl)-benzylidene]-3,4,5,6-tetrahydro-[2,3′]bipyridinyl;-   3-[4-(2,6-Dimethylmorpholin-4-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(4-[1,4]Diazepan-1-ylbenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(4-piperazin-1-ylbenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-[3-(trans-2,5-Dimethylpiperazin-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-[3-(cis-3,5-Dimethylpiperazin-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(3-Thiomorpholin-4-yl-benzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-[3-(2,6-Dimethylmorpholin-4-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(3-[1,4]Diazepan-1-ylbenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-[3-(4-Phenylpiperazin-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-{3-[4-(4-Fluorophenyl)piperazin-1-yl]benzylidene}-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(3-piperazin-1-ylbenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-{3-[(1S,4S)-2,5-Diazabicyclo[2.2.1]hept-2-yl]benzylidene}-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(3-[1,4]Oxazepan-4-ylbenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-[4-(4-Phenylpiperazin-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-{4-[4-(4-Fluorophenyl)piperazin-1-yl]benzylidene}-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-{4-[(1S,4S)-2,5-Diazabicyclo[2.2.1]hept-2-yl]benzylidene}-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(4-[1,4]Oxazepan-4-ylbenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-[4-(3-Methylpiperazin-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-[4-(2-Methylpiperazin-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-[3-(4-Ethylpiperazin-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-[4-(4-Ethylpiperazin-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-[1-(4-Chlorobenzyl)-1H-pyrrol-2-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-[1-(4-Fluorobenzyl)-1H-pyrrol-2-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-[1-(4-Trifluoromethylbenzyl)-1H-pyrrol-2-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-[1-(4-Chlorobenzyl)-1H-pyrazol-3-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-[1-(4-Fluorobenzyl)-1H-pyrazol-3-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-[1-(2,6-Dichlorobenzyl)-1H-pyrrol-2-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-[1-(3,4-Dichlorobenzyl)-1H-pyrrol-2-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-[1-(4-Trifluoromethoxybenzyl)-1H-pyrrol-2-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(1-Biphenyl-4-ylmethyl-1H-pyrrol-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-[1-(2-Fluorobenzyl)-1H-pyrrol-2-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(1-Methylpropyl-1H-pyrrol-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(1-Pyridin-4-ylmethyl-1H-pyrrol-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-[1-(1-Ethylpropyl)-1H-pyrrol-2-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-[1-(2-Chloro-6-fluorobenzyl)-1H-pyrrol-2-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(1-Pentafluorophenylmethyl-1H-pyrrol-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-[1-(2,4,5-Trifluorobenzyl)-1H-pyrrol-2-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(1-Ethyl-1H-pyrazol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-[1-(2-Methylpropyl)-1H-pyrazol-3-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(1-Cyclopropylmethyl-1H-pyrazol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(1-Cyclobutylmethyl-1H-pyrazol-3-ylmethylene)-3,4,5,6-tetrahydro-[2,3′]bipyridinyl;-   3-(1-Cyclohexylmethyl-1H-pyrazol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(1-Cyclopentyl-1H-pyrazol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-[5-Bromo-2-(4-chlorobenzyl)-2H-pyrazol-3-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-[4-(4-Cyclopropylmethylpiperazin-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-[4-(4-Cyclopentylpiperazin-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-{4-[(1S,4S)-5-Methyl-2,5-Diazabicyclo[2.2.1]hept-2-yl]benzylidene}-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-{4-[(1S,4S)-5-Ethyl-2,5-Diazabicyclo[2.2.1]hept-2-yl]benzylidene}-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-{4-[(1S,4S)-5-Cyclopropylmethyl-2,5-Diazabicyclo[2.2.1]hept-2-yl]benzylidene}-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-[4-(4-Methyl[1,4]diazepan-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-[4-(4-Cyclopropylmethyl[1,4]diazepan-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-[4-(4-Cyclopentyl[1,4]diazepan-1-yl)-benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl-   3-[4-(4-Isobutyl-[1,4]diazepan-1-yl)-benzylidene]-3,4,5,6-tetrahydro-[2,3′]bipyridinyl;-   3-{4-[(1S,4S)-5-(2-Methylpropyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]benzylidene}-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-{4-[(1S,4S)-5-Cyclopentyl-2,5-diazabicyclo[2.2.1]hept-2-yl]benzylidene}-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-[4-(4-Ethyl[1,4]diazepan-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   Cyclopropyl-{4-[4-(5,6-dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)phenyl]piperazin-1-yl}methanone;-   1-{4-[4-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)phenyl]piperazin-1-yl}propan-1-one;-   1-{4-[4-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)phenyl]piperazin-1-yl}-2,2,2-trifluoroethanone;-   Cyclopropyl-{(1S,4S)-5-[4-(5,6-dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)phenyl]-2,5-diazabicyclo[2.2.1]hept-2-yl}methanone;-   Cyclopropyl-{4-[4-(5,6-dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)phenyl][1,4]diazepan-1-yl}methanone;-   1-{(1S,4S)-5-[4-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)phenyl]-2,5-diazabicyclo[2.2.1]hept-2-yl}-2,2,2-trifluoroethanone;-   1-{(1S,4S)-5-[4-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)phenyl]-2,5-diazabicyclo[2.2.1]hept-2-yl}propan-1-one;-   1-{4-[4-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)phenyl][1,4]diazepan-1-yl}-2,2,2-trifluoroethanone;-   1-{4-[4-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)phenyl][1,4]diazepan-1-yl}propan-1-one;-   Cyclopropyl-{(1S,4S)-5-[3-(5,6-dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)phenyl]-2,5-diazabicyclo[2.2.1]hept-2-yl}methanone;-   1-{(1S,4S)-5-[3-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)phenyl]-2,5-diazabicyclo[2.2.1]hept-2-yl}-2,2,2-trifluoroethanone;-   Cyclopropyl-{4-[3-(5,6-dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)phenyl]—[1,4]diazepan-1-yl}methanone;-   1-{4-[3-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)phenyl][1,4]diazepan-1-yl}-2,2,2-trifluoroethanone;-   1-{4-[3-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)phenyl]-[1,4]diazepan-1-yl}propan-1-one;-   3-(Benzo[1,3]dioxol-5-ylmethylene)-5′-methyl-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(1H-Indol-3-ylmethylene)-5′-methyl-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   5′-Methyl-3-(1H-pyrrol-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(Benzo[1,3]dioxol-5-ylmethylene)-5′-fluoro-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   5′-Fluoro-3-(1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   5′-Fluoro-3-(1H-pyrrol-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(2,3-Dihydrobenzo[1,4]dioxin-6-ylmethylene)-5′-fluoro-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(1-Cyclopropylmethyl-1H-pyrrol-2-ylmethylene)-5′-fluoro-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   5′-Fluoro-3-(4-morpholin-4-ylbenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(1H-Indol-3-ylmethylene)-6′-trifluoromethyl-3,4,5,6-tetrahydro[2,3′];    and

physiologically acceptable salts thereof.

In addition, in accordance with the invention, preferred compounds arethose described by subformulas I′a-I′i, which correspond to Formula I′,but exhibit the following preferred groups:

-   -   I′a A is dihydrobenzofuranyl, e.g., 2,3-dihydrobenzofuran-5-yl,        which is unsubstituted or substituted by alkyl, alkoxy, halogen,        carboxy, oxo, nitro, alkoxycarbonyl, cyano, trifluoromethyl,        amino, monoalkylamino, dialkylamino, hydroxyl, or hydroxyalkyl.    -   I′b A is dihydrobenzodioxinyl, e.g.,        2,3-dihydrobenzo[1,4]dioxin-6-yl, which is unsubstituted or        substituted by alkyl, alkoxy, halogen, carboxy, oxo, nitro,        alkoxycarbonyl, cyano, trifluoromethyl, amino, monoalkylamino,        dialkylamino, hydroxyl, or hydroxyalkyl.    -   I′c A is chromanyl, e.g., chroman-6-yl, which is unsubstituted        or substituted by alkyl, alkoxy, halogen, carboxy, oxo, nitro,        alkoxycarbonyl, cyano, trifluoromethyl, amino, monoalkylamino,        dialkylamino, hydroxyl, or hydroxyalkyl.    -   I′d A is dihydrobenzodioxepinyl, e.g.,        3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl, which is        unsubstituted or substituted by alkyl, alkoxy, halogen, carboxy,        oxo, nitro, alkoxycarbonyl, cyano, trifluoromethyl, amino,        monoalkylamino, dialkylamino, hydroxyl, or hydroxyalkyl.    -   I′e A is indolyl, e.g., indol-3-yl, indol-4-yl, indol-5-yl,        indol-6-yl, which is unsubstituted or substituted by alkyl,        alkoxy, halogen, carboxy, oxo, nitro, alkoxycarbonyl, cyano,        trifluoromethyl, amino, monoalkylamino, dialkylamino, hydroxyl,        or hydroxyalkyl.    -   I′f A is phenyl substituted by a heterocylic group, e.g.,        4-(4-morpholinyl)-phenyl, which is unsubstituted or substituted        by alkyl, alkoxy, halogen, carboxy, oxo, nitro, alkoxycarbonyl,        cyano, trifluoromethyl, amino, monoalkylamino, dialkylamino,        hydroxyl, or hydroxyalkyl.    -   I′g A is benzoxazinyl, e.g., 3,4-dihydrobenzo[1,4]oxazinyl,        which is unsubstituted or substituted by alkyl, alkoxy, halogen,        carboxy, oxo, nitro, alkoxycarbonyl, cyano, trifluoromethyl,        amino, monoalkylamino, dialkylamino, hydroxyl, or hydroxyalkyl.    -   I′h A is indazolyl, e.g., indazol-3-yl, indazol-5-yl,        indazol-6-yl, which is unsubstituted or substituted by alkyl,        alkoxy, halogen, carboxy, oxo, nitro, alkoxycarbonyl, cyano,        trifluoromethyl, amino, monoalkylamino, dialkylamino, hydroxyl,        or hydroxyalkyl.    -   I′i A is benzoimidazolyl, e.g., benzoimidazol-5-yl, which is        unsubstituted or substituted by alkyl, alkoxy, halogen, carboxy,        oxo, nitro, alkoxycarbonyl, cyano, trifluoromethyl, amino,        monoalkylamino, dialkylamino, hydroxyl, or hydroxyalkyl.

According to a further preferred compound aspect of the invention, thecompound of Formula I′ is selected from:

-   N-[4-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)phenyl]acetamide;-   3-Quinolin-2-ylmethylene-3,4,5,6-terahydro[2,3′]bipyridinyl;-   3-Quinolin-3-ylmethylene-3,4,5,6-terahydro[2,3′]bipyridinyl;-   3-(3,4-Dihydroquinolin-4-ylmethylene)-3,4,5,6-terahydro[2,3′]bipyridinyl;-   3-[1-(Toluene-4-sulfonyl-1H-indol-4-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(1H-indol-4-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(1H-Pyrrol-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl-1H-indole-6-carboxylic    acid Methyl Ester;-   3-(5-Methoxy-1H-Indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(1H-Indol-5-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(6-Benzyloxy-2H-pyrrolo[3,3-c]pyridin-1-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(1-methyl-1H-indol-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(1-methyl-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(4-Benzyloxy-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(2-Methyl-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(3H-Imidazol-4-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(1-Methyl-1H-pyrrol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(5-Fluoro-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(6-Methyl-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(7-Methyl-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(5-Benzyloxy-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(5-Nitro-2-methyl-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   [5-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)benzofuran-2-yl]phenylmethanone;-   6-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)chromen-2-one;-   3-[6-(4-Tolylsulfanyl)pyridin-3-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-[6-(4-Tolyloxy)pyridin-3-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(4-Methanesulfonylbenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(4-Difluoromethoxybenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl    Dihydrochloride;-   3-(4-Phenoxybenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(5′-Bromo-1H,1′H-[2,2′]bipyrrolyl-5-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl    Dihydrochloride;-   5-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)-1H-pyrrole-2-carboxylic    acid Dihydrochloride;-   3-(2,3-Dihydrobenzo[1,4]dioxin-6-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl    Dihydrochloride;-   3-[5-(4-Bromo-phenyl)-thiophen-2-ylmethylene]-3,4,5,6-tetrahydro-[2,3′]bipyridinyl    Dihydrochloride;-   3-[1-(Toluene-4-sulfonyl-1H-indol-3-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl    Dihydrochloride;-   3-[1-Methanesulfonyl-1H-indol-3-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl    Dihydrochloride;-   3-Thiophen-2-ylmethylene-3,4,5,6-tetrahydro[2,3′]bipyridinyl    Dihydrochloride;-   3-Benzofuran-2-ylmethylene-3,4,5,6-tetrahydro[2,3′]bipyridinyl    Dihydrochloride;-   3-(5-Propylthiophen-2-ylmethylene-3,4,5,6-tetrahydro[2,3′]bipyridinyl    Dihydrochloride;-   3-(5-Bromothiophen-2-ylmethylene-3,4,5,6-tetrahydro[2,3′]bipyridinyl    Dihydrochloride;-   3-(5-Methylthiophen-2-ylmethylene-3,4,5,6-tetrahydro[2,3′]bipyridinyl    Dihydrochloride;-   3-(4-Bromo)thiophen-2-ylmethylene-3,4,5,6-tetrahydro[2,3′]bipyridinyl    Dihydrochloride;-   4-[5-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)thiophen-2-yl]phenol    Dihydrobromide;-   3-Benzo[b]thiophen-2-ylmethylene-3,4,5,6-tetrahydro[2,3′]bipyridinyl    Dihydrochloride;-   3-Thiophen-3-ylmethylene-3,4,5,6-tetrahydro[2,3′]bipyridinyl    Dihydrochloride;-   3-Benzo[b]thiophen-3-ylmethylene-3,4,5,6-tetrahydro[2,3′]bipyridinyl    Dihydrochloride;-   3-(4-Allyloxybenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl    Dihydrochloride;-   3-(2,3-Dihydrobenzofuran-5-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl    Dihydrochloride;-   3-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-7-ylmethylene)-3,4,5,6-tetrahydro-[2,3′]bipyridinyl    Dihydrochloride;-   3-(2,2-Dimethylchroman-6-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl    Dihydrochloride;-   3-(2,2-Difluorobenzo[1,3]dioxol-5-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl    Dihydrochloride;-   3-(7-Methoxybenzo[1,3]dioxol-5-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl    Dihydrochloride;-   3-(3-Cyclopentyloxy-4-methoxybenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl    Dihydrochloride;-   3-(4-Methylsulfanylbenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl    Dihydrochloride;-   3-Benzo[1,3]dioxol-5-ylmethylene-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(5-Bromo-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   4-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)-2-nitrophenol;-   3-(1-Methyl-1H-pyrrol-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)cinnoline;-   3-(3-Nitro-4-piperidin-1-ylbenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(4-Pyrazol-1-ylbenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   7-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)-4H-benzo[1,4]oxazin-3-one;-   6-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)-4H-benzo[1,4]oxazin-3-one;-   3-(3-Morpholin-4-ylbenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(3-Pyrrolidin-1-ylbenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-[3-(4-Methylpiperazin-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;    and

physiologically acceptable salts thereof.

Accordingly to a preferred method of use aspect of the invention, thecompound of Formula I′ is selected from:

-   3-Quinolin-2-ylmethylene-3,4,5,6-terahydro[2,3′]bipyridinyl;-   3-Quinolin-3-ylmethylene-3,4,5,6-terahydro[2,3′]bipyridinyl;-   3-(3,4-Dihydroquinolin-4-ylmethylene)-3,4,5,6-terahydro[2,3′]bipyridinyl;-   3-[1-(Toluene-4-sulfonyl-1H-indol-4-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(1H-Indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(1H-Indol-4-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(1H-Pyrrol-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl-1H-indole-6-carboxylic    acid Methyl Ester;-   3-(5-Methoxy-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(1H-Indol-5-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(6-Benzyloxy-2H-pyrrolo[3,3-c]pyridin-1-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(1-Methyl-1H-indol-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(1-Methyl-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(4-Benzyloxy-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(2-Methyl-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(3H-Imidazol-4-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(1-Methyl-1H-pyrrol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(5-Fluoro-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(6-Methyl-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(7-Methyl-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(5-Benzyloxy-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(2-Methyl-5-nitro-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   [5-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)benzofuran-2-yl]phenylmethanone;-   6-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)chromen-2-one;-   3-(5′-Bromo-1H,1′H-[2,2′]bipyrrolyl-5-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl    Dihydrochloride;-   5-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)-1H-thiophene-2-carboxylic    acid Dihydrochloride;-   3-(2,3-Dihydrobenzo[1,4]dioxin-6-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl    Dihydrochloride;-   3-[5-(4-Bromophenyl)-thiophen-2-ylmethylene]-3,4,5,6-tetrahydro-[2,3′]bipyridinyl    Dihydrochloride;-   3-[1-(Toluene-4-sulfonyl-1H-indol-3-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl    Dihydrochloride;-   3-[1-Methanesulfonyl-1H-indol-3-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl    Dihydrochloride;-   3-(Thiophen-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl    Dihydrochloride;-   3-(Benzofuran-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl    Dihydrochloride;-   3-(5-Propylthiophen-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl    Dihydrochloride;-   3-(5-Bromothiophen-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl    Dihydrochloride;-   3-(5-Methylthiophen-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl    Dihydrochloride;-   3-(4-Bromothiophen-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl    Dihydrochloride;-   4-[5-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)thiophen-2-yl]phenol    Dihydrobromide;-   3-(Benzo[b]thiophen-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl    Dihydrochloride;-   3-(Thiophen-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl    Dihydrochloride;-   3-(Benzo[b]thiophen-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl    Dihydrochloride;-   3-(2,3-Dihydrobenzofuran-5-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl    Dihydrochloride;-   3-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-7-ylmethylene)-3,4,5,6-tetrahydro-[2,3′]bipyridinyl    Dihydrochloride;-   3-(2,2-Dimethylchroman-6-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl    Dihydrochloride;-   3-(2,2-Difluorobenzo[1,3]dioxol-5-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl    Dihydrochloride;-   3-(7-Methoxybenzo[1,3]dioxol-5-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl    Dihydrochloride;-   3-(Benzo[1,3]dioxol-5-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(5-Bromo-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   4-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)-2-nitrophenol;-   3-(1-Methyl-1H-pyrrol-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)cinnoline;-   3-(3-Nitro-4-piperidin-1-ylbenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(4-(Pyrazol-1-yl)benzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   7-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)-4H-benzo[1,4]oxazin-3-one;-   6-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)-4H-benzo[1,4]oxazin-3-one;-   3-(3-Morpholin-4-ylbenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-(3-Pyrrolidin-1-ylbenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;-   3-[3-(4-Methylpiperazin-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;    and

physiologically acceptable salts thereof.

A preferred starting materials for use in the synthesis of compounds offormula I is 3-(4-iodobenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyland is 3-(3-iodobenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl.

The preferred aspects include pharmaceutical compositions comprising acompound of this invention and a pharmaceutically acceptable carrierand, optionally, another active agent as discussed below; a method ofstimulating or activating inhibiting alpha-7 nicotinic receptors, e.g.,as determined by a conventional assay or one described herein, either invitro or in vivo (in an animal, e.g., in an animal model, or in a mammalor in a human); a method of treating a neurological syndrome, e.g., lossof memory, especially long-term memory, cognitive impairment or decline,memory impairment, etc. method of treating a disease state modulated bynicotinic alpha-7 activity, in a mammal, e.g., a human, e.g., thosementioned herein.

The compounds of the present invention may be prepared conventionally.Some of the known processes that can be used are described below. Allstarting materials are known or can be conventionally prepared fromknown starting materials.

The aldehydes used in the preparation of the nicotinic ligands arecommercially available or were prepared by literature procedures. Forexample, 5-formylbenzimidazole can be prepared by benzylic oxidation ofthe 5-methyl precursor. [Talaty, C. N.; Zenker, N.; Callery, P. S.Oxidation of Methylbenzimidazoles with Ceric Ammonium Nitrate. JHeterocyclic Chem. 1976, 1121-1123]. 5-Formyl-2-oxobenzimidazole can beprepared from methyl 3,4-diaminobenzoate by urethane formation followedby a reduction/oxidation sequence. [Schmidt, G.; Zeiler, H.-J.; Metzger,K. G. Novel β-Lactam Antibiotics. U.S. Pat. No. 4,748,163, May 31,1988.] 5-Formylindazole can be prepared from 4-bromo-2-methylaniline bydiazotization followed by metal-halogen exchange and trapping with aformamide. [DeLucca, G. V. Substituted 2H-1,3-Diazapin-2-one Useful asan HIV Protease Inhibitor. U.S. Pat. No. 6,313,110 B1, Nov. 6, 2001.]5-Formylbenzothiophene can be prepared from 4-bromothiophenol byS-alkylation with an acetaldehyde equivalent followed by cyclization,metal-halogen exchange, and trapping with at formamide. [Barker, P.;Finke, P.; Thompsom, K. Synth. Comm. 1989, 257-265.]

The nicotinic ligands can be prepared by the condensation of anabasinewith an excess of the requisite aldehydes under either acidic or mildlyacidic, buffered conditions. [Kem, W. R.; Zoltewicz, J. A.; Meyer, E.M.; Katalin, P.-T. Anabasine Derivatives Useful in the Treatment ofDegeneratives Diseases of the Nervous System. U.S. Pat. No. 5,741,802,Apr. 21, 1998.] The condensations are generally performed at elevatedtemperatures for 24 hours. The resultant adducts of Formula I or FormulaI′ can be isolated and purified by standard techniques, such aschromatography or recrystallization, practiced by those skilled in theart.

The nicotinic ligands can, alternatively, be prepared by modification ofother nicotinic ligands. For example, the benzoxazol-2-one ligand wasprepared from the corresponding nitro phenol ligand by selectivereduction and carbamate formation. The 3-(3-Morpholin-4-ylbenzylidene)ligand was prepared from the corresponding iodide ligand by apalladium-catalyzed amination [see, e.g., Ali, M. H.; Buchwald, S. L. AnImproved Method for the Palladium-Catalyzed Amination of Aryl Iodides.J. Org. Chem. 2001, 66, 2560-2565].

One of ordinary skill in the art will recognize that some of thecompounds of Formula I or Formula I′ can exist in different tautomericand geometrical isomeric forms. All of these compounds, including cisisomers, trans isomers, diastereomic mixtures, racemates, nonracemicmixtures of enantiomers, substantially pure, and pure enantiomers, arewithin the scope of the present invention. Substantially pureenantiomers contain no more than 5% w/w of the corresponding oppositeenantiomer, preferably no more than 2%, most preferably no more than 1%.

The optical isomers can be obtained by resolution of the racemicmixtures according to conventional processes, for example, by theformation of diastereoisomeric salts using an optically active acid orbase or formation of covalent diastereomers. Examples of appropriateacids are tartaric, diacetyltartaric, dibenzoyltartaric,ditoluoyltartaric and camphorsulfonic acid. Mixtures of diastereoisomerscan be separated into their individual diastereomers on the basis oftheir physical and/or chemical differences by methods known to thoseskilled in the art, for example, by chromatography or fractionalcrystallization. The optically active bases or acids are then liberatedfrom the separated diastereomeric salts. A different process forseparation of optical isomers involves the use of chiral chromatography(e.g., chiral HPLC columns), with or without conventional derivation,optimally chosen to maximize the separation of the enantiomers. Suitablechiral HPLC columns are manufactured by Diacel, e.g., Chiracel OD andChiracel OJ among many others, all routinely selectable. Enzymaticseparations, with or without derivitization, are also useful. Theoptically active compounds of Formula I or Formula I′ can likewise beobtained by utilizing optically active starting materials in chiralsynthesis processes under reaction conditions which do not causeracemization.

In addition, one of ordinary skill in the art will recognize that thecompounds can be used in different enriched isotopic forms, e.g.,enriched in the content of ²H, ³H, ¹¹C, ¹³C and/or ¹⁴C. In oneparticular embodiment, the compounds are deuterated. Such deuteratedforms can be made the procedure described in U.S. Pat. Nos. 5,846,514and 6,334,997. As described in U.S. Pat. Nos. 5,846,514 and 6,334,997,deuteration can improve the efficacy and increase the duration of actionof drugs.

Deuterium substituted compounds can be synthesized using various methodssuch as described in: Dean, Dennis C.; Editor. Recent Advances in theSynthesis and Applications of Radiolabeled Compounds for Drug Discoveryand Development [In: Curr., Pharm. Des., 2000; 6(10)] (2000), 110 pp.CAN 133:68895 AN 2000:473538 CAPLUS; Kabalka, George W.; Varma, RajenderS. The synthesis of radiolabeled compounds VIA organometallicintermediates. Tetrahedron (1989), 45(21), 6601-21, CODEN: TETRABISSN:0040-4020. CAN 112:20527 AN 1990:20527 CAPLUS; and Evans, E.Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem.(1981), 64(1-2), 9-32. CODEN: JRACBN ISSN:0022-4081, CAN 95:76229 AN1981:476229 CAPLUS.

Where applicable, the present invention also relates to useful forms ofthe compounds as disclosed herein, such as pharmaceutically acceptablesalts or prodrugs of all the compounds of the present invention forwhich salts or prodrugs can be prepared. Pharmaceutically acceptablesalts include those obtained by reacting the main compound, functioningas a base, with an inorganic or organic acid to form a salt, forexample, salts of hydrochloric acid, sulfuric acid, phosphoric acid,methane sulfonic acid, camphor sulfonic acid, oxalic acid, maleic acid,succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid,tartaric acid, fumaric acid, salicylic acid, mandelic acid, and carbonicacid. Pharmaceutically acceptable salts also include those in which themain compound functions as an acid and is reacted with an appropriatebase to form, e.g., sodium, potassium, calcium, magnesium, ammonium, andcholine salts. Those skilled in the art will further recognize that acidaddition salts of the claimed compounds may be prepared by reaction ofthe compounds with the appropriate inorganic or organic acid via any ofa number of known methods. Alternatively, alkali and alkaline earthmetal salts can be prepared by reacting the compounds of the inventionwith the appropriate base via a variety of known methods.

The following are further examples of acid salts that can be obtained byreaction with inorganic or organic acids: acetates, adipates, alginates,citrates, aspartates, benzoates, benzenesulfonates, bisulfates,butyrates, camphorates, digluconates, cyclopentanepropionates,dodecylsulfates, ethanesulfonates, glucoheptanoates, glycerophosphates,hemisulfates, heptanoates, hexanoates, fumarates, hydrobromides,hydroiodides, 2-hydroxy-ethanesulfonates, lactates, maleates,methanesulfonates, nicotinates, 2-naphthalenesulfonates, oxalates,palmoates, pectinates, persulfates, 3-phenylpropionates, picrates,pivalates, propionates, succinates, tartrates, thiocyanates, tosylates,mesylates and undecanoates.

Preferably, the salts formed are pharmaceutically acceptable foradministration to mammals. However, pharmaceutically unacceptable saltsof the compounds are suitable as intermediates, for example, forisolating the compound as a salt and then converting the salt back tothe free base compound by treatment with an alkaline reagent. The freebase can then, if desired, be converted to a pharmaceutically acceptableacid addition salt.

The compounds of the invention can be administered alone or as an activeingredient of a formulation. Thus, the present invention also includespharmaceutical compositions of compounds of Formula I or Formula I′,containing, for example, one or more pharmaceutically acceptablecarriers.

Numerous standard references are available that describe procedures forpreparing various formulations suitable for administering the compoundsaccording to the invention. Examples of potential formulations andpreparations are contained, for example, in the Handbook ofPharmaceutical Excipients, American Pharmaceutical Association (currentedition); Pharmaceutical Dosage Forms: Tablets (Lieberman, Lachman andSchwartz, editors) current edition, published by Marcel Dekker, Inc., aswell as Remington's Pharmaceutical Sciences (Arthur Osol, editor),1553-1593 (current edition).

In view of their alpha-7 stimulating activity and, preferably their highdegree of selectivity, the compounds of the present invention can beadministered to anyone needing stimulation of alpha-7 receptors.Administration may be accomplished according to patient needs, forexample, orally, nasally, parenterally (subcutaneously, intravenously,intramuscularly, intrasternally and by infusion) by inhalation,rectally, vaginally, topically and by ocular administration.

Various solid oral dosage forms can be used for administering compoundsof the invention including such solid forms as tablets, gelcaps,capsules, caplets, granules, lozenges and bulk powders. The compounds ofthe present invention can be administered alone or combined with variouspharmaceutically acceptable carriers, diluents (such as sucrose,mannitol, lactose, starches) and excipients known in the art, includingbut not limited to suspending agents, solubilizers, buffering agents,binders, disintegrants, preservatives, colorants, flavorants, lubricantsand the like. Time release capsules, tablets and gels are alsoadvantageous in administering the compounds of the present invention.

Various liquid oral dosage forms can also be used for administeringcompounds of the inventions, including aqueous and non-aqueoussolutions, emulsions, suspensions, syrups, and elixirs. Such dosageforms can also contain suitable inert diluents known in the art such aswater and suitable excipients known in the art such as preservatives,wetting agents, sweeteners, flavorants, as well as agents foremulsifying and/or suspending the compounds of the invention. Thecompounds of the present invention may be injected, for example,intravenously, in the form of an isotonic sterile solution. Otherpreparations are also possible.

Suppositories for rectal administration of the compounds of the presentinvention can be prepared by mixing the compound with a suitableexcipient such as cocoa butter, salicylates and polyethylene glycols.Formulations for vaginal administration can be in the form of a pessary,tampon, cream, gel, paste, foam, or spray formula containing, inaddition to the active ingredient, such suitable carriers as are knownin the art.

For topical administration the pharmaceutical composition can be in theform of creams, ointments, liniments, lotions, emulsions, suspensions,gels, solutions, pastes, powders, sprays, and drops suitable foradministration to the skin, eye, ear or nose. Topical administration mayalso involve transdermal administration via means such as transdermalpatches.

Aerosol formulations suitable for administering via inhalation also canbe made. For example, for treatment of disorders of the respiratorytract, the compounds according to the invention can be administered byinhalation in the form of a powder (e.g., micronized) or in the form ofatomized solutions or suspensions. The aerosol formulation can be placedinto a pressurized acceptable propellant.

The compounds can be administered as the sole active agent or incombination with other pharmaceutical agents such as other agents usedin the treatment of cognitive impairment and/or memory loss, e.g., otherα-7 agonists, PDE4 inhibitors, calcium channel blockers, muscarinic m1and m2 modulators, adenosine receptor modulators, amphakines NMDA-Rmodulators, mGluR modulators, dopamine modulators, serotonin modulators,canabinoid modulators, and cholinesterase inhibitors (e.g., donepezil,rivastigimine, and glanthanamine). In such combinations, each activeingredient can be administered either in accordance with their usualdosage range or a dose below their usual dosage range.

The compounds of the invention can be used in conjunction with “positivemodulators” which enhance the efficacy of nicotinic receptor agonists.See, e.g., the positive modulators disclosed in WO 99/56745, WO01/32619, and WO 01/32622. Such combinational therapy can be used intreating conditions/diseases associated with reduced nicotinictransmission.

Further the compounds may be used in conjunction with compounds thatbind to Aβ peptides and thereby inhibit the binding of the peptides toα7nAChr subtypes. See, e.g., WO 99/62505.

The present invention further includes methods of treatment that involveactivation of α-7 nicotinic receptors. Thus, the present inventionincludes methods of selectively activating/stimulating α-7 nicotinicreceptors in animals, e.g., mammals, especially humans, wherein suchactivation/stimulation has a therapeutic effect, such as where suchactivation may relieve conditions involving neurological syndromes, suchas the loss of memory, especially long-term memory. Such methodscomprise administering to an animal in need thereof, especially amammal, most especially a human, an effective amount of a compound ofFormula I or Formula I′, alone or as part of a formulation, as disclosedherein.

Agents that bind to nicotinic acetylcholine receptors have beenindicated as useful in the treatment and/or prophylaxis of variousdiseases and conditions, particularly psychotic diseases,neurodegenerative diseases involving a dysfunction of the cholinergicsystem, and conditions of memory and/or cognition impairment, including,for example, schizophrenia, anxiety, mania, depression, manic depression[examples of psychotic disorders], Tourette's syndrome, Parkinson'sdisease, Huntington's disease [examples of neurodegenerative diseases],cognitive disorders (such as Alzheimer's disease, Lewy Body Dementia,Amyotrophic Lateral Sclerosis, memory impairment, memory loss, cognitiondeficit, attention deficit, Attention Deficit Hyperactivity Disorder),and other uses such as treatment of nicotine addiction, inducing smokingcessation, treating pain (i.e., analgesic use), providingneuroprotection, and treating jetlag. See, e.g., WO 97/30998; WO99/03850; WO 00/42044; WO 01/36417; Holladay et al., J. Med. Chem.,40:26, 4169-94 (1997); Schmitt et al., Annual Reports Med. Chem.,Chapter 5, 41-51 (2000); and Stevens et al., Psychopharmatology, (1998)136: 320-27 (1998).

Thus, in accordance with the invention, there is provided a method oftreating a patient, especially a human, suffering from psychoticdiseases, neurodegenerative diseases involving a dysfunction of thecholinergic system, and conditions of memory and/or cognitionimpairment, including, for example, schizophrenia, anxiety, mania,depression, manic depression [examples of psychotic disorders],Tourette's syndrome, Parkinson's disease, Huntington's disease [examplesof neurodegenerative diseases], and/or cognitive disorders (such asAlzheimer's disease, Lewy Body Dementia, Amyotrophic Lateral Sclerosis,memory impairment, memory loss, cognition deficit, attention deficit,Attention Deficit Hyperactivity Disorder) comprising administering tothe patient an effective amount of a compound according to Formula I orFormula I′.

Neurodegenerative disorders included within the methods of the presentinvention include, but are not limited to, treatment and/or prophylaxisof Alzheimer's diseases, Pick's disease, diffuse Lewy Body disease,progressive supranuclear palsy (Steel-Richardson syndrome), multisystemdegeneration (Shy-Drager syndrome), motor neuron diseases includingamyotrophic lateral sclerosis, degenerative ataxias, cortical basaldegeneration, ALS-Parkinson's-Dementia complex of Guam, subacutesclerosing panencephalitis, Huntington's disease, Parkinson's disease,synucleinopathies, primary progressive aphasia, striatonigraldegeneration, Machado-Joseph disease/spinocerebellar ataxia type 3,olivopontocerebellar degenerations, Gilles De La Tourette's disease,bulbar, pseudobulbar palsy, spinal muscular atrophy, spinobulbarmuscular atrophy (Kennedy's disease), primary lateral sclerosis,familial spastic paraplegia, Werdnig-Hoffmann disease,Kugelberg-Welander disease, Tay-Sach's disease, Sandhoff disease,familial spastic disease, Wohlfart-Kugelberg-Welander disease, spasticparaparesis, progressive multifocal leukoencephalopathy, prion diseases(such as Creutzfeldt-Jakob, Gerstmann-Sträussler-Scheinker disease, Kuruand fatal familial insomnia), and neurodegenerative disorders resultingfrom cerebral ischemia or infarction including embolic occlusion andthrombotic occlusion as well as intracranial hemorrhage of any type(including, but not limited to, epidural, subdural, subarachnoid andintracerebral), and intracranial and intravertebral lesions (including,but not limited to, contusion, penetration, shear, compression andlaceration).

In addition, α-7nAChRs agonists, such as the compounds of the presentinvention can be used to treat age-related dementia and other dementiasand conditions with memory loss including age-related memory loss,senility, vascular dementia, diffuse white matter disease (Binswanger'sdisease), dementia of endocrine or metabolic origin, dementia of headtrauma and diffuse brain damage, dementia pugilistica and frontal lobedementia. See, e.g., WO 99/62505. Thus, in accordance with theinvention, there is provided a method of treating a patient, especiallya human, suffering from age-related dementia and other dementias andconditions with memory loss comprising administering to the patient aneffective amount of a compound according to Formula I or Formula I′.

Thus, in accordance with a further embodiment, the present inventionincludes methods of treating patients suffering from memory impairmentdue to, for example, mild cognitive impairment due to aging, Alzheimer'sdisease, schizophrenia, Parkinson's disease, Huntington's disease,Pick's disease, Creutzfeld-Jakob disease, depression, aging, headtrauma, stroke, CNS hypoxia, cerebral senility, multiinfarct dementiaand other neurological conditions, as well as HIV and cardiovasculardiseases, comprising administering an effective amount of a compoundaccording to Formula I or Formula I′.

Amyloid precursor protein (APP) and Aβ peptides derived therefrom, e.g.,Aβ₁₋₄₀, Aβ₁₋₄₂, and other fragments, are known to be involved in thepathology of Alzheimer's disease. The Aβ₁₋₄₂ peptides are not onlyimplicated in neurotoxicity but also are known to inhibit cholinergictransmitter function. Further, it has been determined that Aβ peptidesbind to α7 nAChRs. Thus, agents which block the binding of the Aβpeptides to α-7 nAChRs are useful for treating neurodegenerativediseases. See, e.g., WO 99/62505. In addition, stimulation α-7 nAChRscan protect neurons against cytotoxicity associated with Aβ peptides.See, e.g., Kihara, T. et al., Ann. Neurol., 1997, 42, 159.

Thus, in accordance with an embodiment of the invention there isprovided a method of treating and/or preventing dementia in anAlzheimer's patient which comprises administering to the subject atherapeutically effective amount of a compound according to Formula I orFormula I′ to inhibit the binding of an amyloid beta peptide(preferably, Aβ₁₋₄₂) with nAChRs, preferable α-7 nAChRs, mostpreferably, human α-7 nAChRs (as well as a method for treating and/orpreventing other clinical manifestations of Alzheimer's disease thatinclude, but are not limited to, cognitive and language deficits,apraxias, depression, delusions and other neuropsychiatric symptoms andsigns, and movement and gait abnormalities).

The present invention also provides methods for treating otheramyloidosis diseases, for example, hereditary cerebral angiopathy,nonneuropathic hereditary amyloid, Down's syndrome, macroglobulinemia,secondary familial Mediterranean fever, Muckle-Wells syndrome, multiplemyeloma, pancreatic- and cardiac-related amyloidosis, chronichemodialysis anthropathy, Finnish and Iowa amyloidosis, and eye disease.

In addition, nicotinic receptors have been implicated as playing a rolein the body's response to alcohol ingestion. Thus, agonists forα-7nAChR's can be used in the treatment of alcohol withdrawal and inanti-intoxication therapy. Thus, in accordance with an embodiment of theinvention there is provided a method of treating a patient for alcoholwithdrawal or treating a patient with anti-intoxication therapycomprising administering to the patient an effective amount of acompound according to Formula I or Formula I′.

Agonists for the α-7nAChR subtypes can also be used for neuroprotectionagainst damage associated with strokes and ischemia andglutamate-induced excitotoxicity. Thus, in accordance with an embodimentof the invention there is provided a method of treating a patient toprovide for neuroprotection against damage associated with strokes andischemia and glutamate-induced excitotoxicity comprising administeringto the patient an effective amount of a compound according to Formula Ior Formula I′.

As noted above, agonists for the α-7nAChR subtypes can also be used inthe treatment of nicotine addiction, inducing smoking cessation,treating pain, and treating jetlag, obesity, diabetes, and inflammation.Thus, in accordance with an embodiment of the invention there isprovided a method of treating a patient suffering from nicotineaddiction, pain, jetlag, obesity, diabetes, and/or inflammation, or amethod of inducing smoking cessation in a patient comprisingadministering to the patient an effective amount of a compound accordingto Formula I or Formula I′.

In addition, due to their affinity to α-7nAChR's, labeled derivatives ofthe compounds of Formula I or Formula I′ (e.g., C¹¹ or F¹⁸ labelledderivatives), can be used in neuroimaging of the receptors within, e.g.,the brain. Thus, using such labeled agents in vivo imaging of thereceptors can be performed using, e.g., PET imaging.

The condition of memory impairment is manifested by impairment of theability to learn new information and/or the inability to recallpreviously learned information. Memory impairment is a primary symptomof dementia and can also be a symptom associated with such diseases asAlzheimer's disease, schizophrenia, Parkinson's disease, Huntington'sdisease, Pick's disease, Creutzfeld-Jakob disease, HIV, cardiovasculardisease, and head trauma as well as age-related cognitive decline.

Thus, in accordance with an embodiment of the invention there isprovided a method of treating a patient suffering from, for example,mild cognitive impairment (MCI), vascular dementia (VaD), age-associatedcognitive decline (AACD), amnesia associated w/open-heart-surgery,cardiac arrest, and/or general anesthesia, memory deficits from earlyexposure of anesthetic agents, sleep deprivation induced cognitiveimpairment, chronic fatigue syndrome, narcolepsy, AIDS-related dementia,epilepsy-related cognitive impairment, Down's syndrome, Alcoholismrelated dementia, drug/substance induced memory impairments, DementiaPuglistica (Boxer Syndrome), and animal dementia (e.g. dogs, cats,horses, etc.) patient comprising administering to the patient aneffective amount of a compound according to Formula I or Formula I′.

The dosages of the compounds of the present invention depend upon avariety of factors including the particular syndrome to be treated, theseverity of the symptoms, the route of administration, the frequency ofthe dosage interval, the particular compound utilized, the efficacy,toxicology profile, pharmacokinetic profile of the compound, and thepresence of any deleterious side-effects, among other considerations.

The compounds of the invention can be administered to mammals,particularly humans, at typical dosage levels customary for α-7nicotinic receptor agonists such as the known α-7 nicotinic receptoragonist compounds mentioned above. For example, the compounds can beadministered, in single or multiple doses, by oral administration at adosage level of, for example, 0.0001-10 mg/kg/day, e.g., 0.01-10mg/kg/day. Unit dosage forms can contain, for example, 1-200 mg ofactive compound. For intravenous administration, the compounds can beadministered, in single or multiple dosages.

In carrying out the procedures of the present invention it is of courseto be understood that reference to particular buffers, media, reagents,cells, culture conditions and the like are not intended to be limiting,but are to be read so as to include all related materials that one ofordinary skill in the art would recognize as being of interest or valuein the particular context in which that discussion is presented. Forexample, it is often possible to substitute one buffer system or culturemedium for another and still achieve similar, if not identical, results.Those of skill in the art will have sufficient knowledge of such systemsand methodologies so as to be able, without undue experimentation, tomake such substitutions as will optimally serve their purposes in usingthe methods and procedures disclosed herein.

The present invention will now be further described by way of thefollowing non-limiting examples. In applying the disclosure of theseexamples, it should be kept clearly in mind that other and differentembodiments of the methods disclosed according to the present inventionwill no doubt suggest themselves to those of skill in the relevant art.

In the foregoing and in the following examples, all temperatures are setforth uncorrected in degrees Celsius; and, unless otherwise indicated,all parts and percentages are by weight.

The entire disclosures of all applications, patents and publications,cited above and below, are hereby incorporated by reference.

EXAMPLES

All spectra were recorded at 300 MHz on a Bruker Instruments NMR.Coupling constants (J) are in Hertz (Hz) and peaks are listed relativeto TMS (δ 0.00 ppm). Microwave reactions were performed using a PersonalChemistry Optimizer™ microwave reactor in 2.5 mL or 5 mL PersonalChemistry microwave reactor vials. All reactions were performed at 200°C. for 600 s with the fixed hold time ON unless otherwise stated.Sulfonic acid ion exchange resins (SCX) were purchased from VarianTechnologies.

Representative Procedure A: Example 13-(1H-Indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl from1H-indol-3-carbaldehyde

To a solution of 50.0 mg (0.220 mmol) anabaseine dihydrochloride in abuffer solution of 0.6 M acetic acid/0.3 M sodium acetate in methanol(1.5 ml) was added indole-3-carbaldehyde (63.9 mg, 0.440 mmol, 2.0 eq).The mixture was kept at 60° C. for 18 h and then poured into ice water.The solution was washed with dichloromethane, was made basic (pH 9-10)by the addition of a saturated, aqueous sodium carbonate solution, andwas extracted with ethyl acetate (3×). The combined ethyl acetate layerswere washed with brine, dried over anhydrous sodium sulfate, andconcentrated. The residue was purified by chromatography [1/1 to 0/1ethyl acetate/(70/30/1 ethyl acetate/methanol/ammonium hydroxide)] toprovide 31.6 mg (50%) of the product Data: ¹H NMR (CDOD₃) δ 12.51 (s,1H), 9.46 (m, 2H), 8.69 (m, 1H), 8.52 (s, 1H), 8.29 (m, 2H), 8.04 (m,1H), 7.93 (m, 1H), 7.83 (m, 1H), 7.65 (s, 1H), 4.50 (m, 2H), 3.56 (s,2H), 2.60 (m, 2H); MS (EI) m/z 288 (M⁺+1).

Using this general procedure the following compounds were prepared:

Example 23-[1-(Toluene-4-sulfonyl-1H-indol-4-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 1-(toluene-4-sulfonyl)-1H-indole-4-carbaldehyde

Yield 50%. ¹H NMR (DMSO-d₆) δ 8.64 (m, 2H), 7.86 (m, 5H), 7.38 (m, 5H),6.74 (s, 1H), 6.60 (m, 1H), 3.42 (m, 2H), 2.65 (m, 2H), 2.48 (s, 3H),1.69 (m, 2H); MS (EI) m/z 442 (M⁺+1).

Example 3 3-(1H-Indol-4-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 1H-indol-4-carbaldehyde

Yield: 50%. ¹H NMR (CDOD₃) δ 8.65 (m, 2H), 7.95 (m, 1H), 7.64 (s, 1H),7.55 (m, 1H), 7.37 (d, J=9.0, 1H), 7.26 (m, 1H), 7.12 (d, J=9.0, 1H),6.80 (m, 1H), 6.47 (m, 1H), 3.81 (m, 2H), 3.02 (m, 2H), 1.91 (m, 2H); MS(EI) m/z 288 (M⁺+1).

Example 43-(1H-Pyrrol-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl from1H-pyrrole-2-carbaldehyde

Yield: 40%. ¹H NMR (DMSO-d₆) δ 11.09 (s, 1H), 8.60 (m, 2H), 7.80 (m,1H), 7.44 (m, 1H), 6.91 (m, 1H), 6.50 (m, 1H), 6.42 (m, 1×), 6.19 (m,1H), 3.65 (m, 2H), 2.65 (m, 2H), 1.75 (m, 2H); MS (EI) m/z 238 (M⁺+1).

Example 53-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl-1H-indole-6-carboxylicacid Methyl Ester from 3-formyl-1H-indole-6-carboxylic Acid Methyl Ester

Yield: 60%. ¹H NMR (CD₃OD) δ 8.68 (m, 2H), 8.14 (m, 1H), 7.98 (m, 1H),7.88 (m, 1H), 7.73 (m, 1H), 7.61 (m, 1H), 7.33 (m, 1H), 6.96 (m, 1H),3.90 (s, 3H), 3.78 (m, 2H), 2.89 (m, 2H), 1.96 (in 2H); MS (EI) m/z 346(M⁺+1).

Example 63-(5-Methoxy-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 5-methoxy-1H-indole-3-carbaldehyde

Yield: 55%. ¹H NMR (CD₃OD) δ 8.67 (m, 2H), 7.98 (m, 1H), 7.63 (m, 2H),7.30 (d, J=9.0, 1H), 6.93 (m, 1H), 6.83 (m, 1H), 6.70 (m, 1H), 3.76 (m,2H), 3.72 (s, 3H), 2.86 (m, 2H), 1.96 (m, 2H); MS (EI) m/z 318 (M⁺+1).

Example 7 3-(1H-Indol-5-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 1H-indole-5-carbaldehyde

Yield: 60%. ¹H NMR (CD₃OD) δ 8.63 (m, 2H), 7.94 (m, 1H), 7.62 (s, 1H),7.54 (m, 1H), 7.37 (d, J=9.0, 1H), 7.25 (m, 1H), 7.10 (m, 1H), 6.76 (s,1H), 6.47 (m, 1H), 3.81 (m, 2H), 3.01 (m, 2H), 1.89 (m, 2H); MS (EI) m/z288 (M⁺+1).

Example 83-(5-Benzyloxy-6-aza-1H-indol[3,3-c]pyridin-1-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 5-benzyloxy-1H-6-aza-indol-3-carbaldehyde

Yield: 55%. ¹H NMR (CD₃OD) δ 8.68 (m, 2H), 8.34 (m, 1H), 7.97 (m, 1H),7.88 (m, 1H), 7.59 (m, 1H), 7.36 (m, 5H), 6.81 (m, 1H), 6.64 (m, 1H),5.25 (s, 2H), 3.77 (m, 2H), 2.82 (m, 2H), 1.94 (m, 2H); MS (EI) m/z 395(M⁺+1).

Example 93-(1-Methyl-1H-indol-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 1-methyl-1H-indol-2-carbaldehyde

Yield: 50%. ¹H NMR (CD₃OD) δ 8.69 (m, 2H), 8.01 (m, 1H), 7.60 (m, 2H),7.33 (m, 1H), 7.21 (m, 1H), 7.06 (m, 1H), 6.88 (s, 1H), 6.77 (s, 1H),3.84 (m, 2H), 3.53 (s, 3H), 2.98 (m, 2H), 1.95 (m, 2H), MS (EI) m/z 302(M⁺+1).

Example 103-(1-Methyl-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 1-methyl-1H-indol-3-carbaldehyde

Yield %. ¹H NMR (CD₃OD) δ 8.67 (m, 2H), 7.99 (m, 1H), 7.65 (s, 1H), 7.60(m, 1H), 7.42 (m, 1H), 7.24 (m, 2H), 7.07 (m, 1H), 6.96 (m, 1H), 3.90(s, 3H), 3.76 (m, 2H), 2.87 (m, 2H), 2.00 (m, 2H); MS (EI) m/z 302(M⁺+1).

Example 113-(4-Benzyloxy-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 4-benzyloxy-1H-indol-3-carbaldehyde

Yield: 50%. ¹H NMR (CD₃OD) δ 8.60 (m, 1H), 8.43 (m, 1H), 7.86 (m, 1H),7.81 (m, 1H), 7.56 (m, 1H), 7.27 (m, 4H), 7.14 (m, 2H), 6.97 (m, 2H),6.50 (m, 1H), 5.01 (s, 2H), 3.75 (m, 2H), 2.84 (m, 2H), 1.95 (m, 2H); MS(EI m/z 394 (M⁺+1).

Example 123-(2-Methyl-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 2-methyl-1H-indol-3-carbaldehyde

Yield: 55%. ¹H NMR (CD₃OD) δ 8.67 (m, 1H), 8.62 (m, 1H), 7.98 (m, 1H),7.54 (m, 1H), 7.30 (m, 2H), 7.05 (m, 2H), 6.76 (s, 1H), 3.87 (m, 2H),2.69 (m, 2H), 2.29 (s, 3H), 1.87 (m, 2H); MS (EI) m/z 303 (M⁺+2).

Example 133-(5-Chloro-1H-indo)-3-ylmethylene)-3,4,5,6-tetrahydro-[2,3′]bipyridinylfrom 5-chloro-1H-indole-3-carbaldehyde

Yield, 60%. ¹H NMR (CD₃OD) δ 8.70 (m, 2H), 8.00 (m, 1H), 7.72 (s, 1H),7.60 (m, 1H), 7.38 (m, 1H), 7.19 (m, 1H), 7.17 (m, 1H), 6.87 (m, 1H),3.78 (m, 2H), 2.86 (m, 2H), 1.95 (m, 2H); MS (EI) m/z 322 (M⁺+1).

Example 143-(5-Nitro-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 5-nitro-1H-indole-3-carbaldehyde

Yield: 40%. ¹H NMR (CD₃OD) δ 8.67 (m, 2H), 8.21 (m, 1H), 7.97 (m, 3H),7.54 (m, 2H), 6.87 (m, 1H), 3.70 (m, 2H), 2.75 (m, 2H), 1.77 (m, 2H); MS(EI) m/z 333 (M⁺+1).

Example 153-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)-9-ethyl-9H-carbazolefrom 9-ethyl-9H-carbazole-3-carbaldehyde

Yield: 40%. ¹H NMR (CD₃OD) δ 8.66 (m, 2H), 8.12 (m, 2H, 7.97 (m, 1H),7.54 (m, 4H), 7.20 (m, 1H), 6.85 (m, 1H), 4.43 (m, 2H), 3.84 (m, 2H),3.09 (m, 2H), 1.93 (m, 2H), 1.41 (m, 3H); MS (EI) m/z 366 (M⁺+1).

Example 163-(1-Benzyl-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 1-benzyl-1H-indole-3-carbaldehyde

Yield: 60%. ¹H NMR (CD₃OD) δ 8.68 (m, 2H), 7.98 (m, 1H), 7.79 (s, 1H),7.59 (m, 1H), 7.26 (m, 1H), 5.49 (s, 2H), 3.78 (m, 2H), 2.86 (m, 2H),1.95 (m, 2H); MS (EI) m/z 378 (M⁺+1).

Example 173-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)-9-ethyl-9H-carbazoledihydrochloride from 9-ethyl-9H-carbazole-3-carbaldehyde

Yield: 40%. ¹H NMR (DMSO-d6) δ 8.93 (m, 2H), 8.87 (m, 1H), 8.52 (m, 1H),8.25 (m, 1H), 8.24 (m, 1H), 7.75 (m, 4H), 7.53 (m, 2H), 7.27 (m, 1H),4.53 (in 2H), 3.38 (m, 2H), 3.18 (m, 2H), 2.20 (m, 2H), 1.31 (m, 3H); MS(EI) m/z 366 (M′+1).

Example 183-(1H-indol-6-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl from1H-indole-6-carbaldehyde

Yield: 60%. ¹H NMR (CD₃OD) δ 8.63 (m, 2H), 7.95 (m, 1H), 7.54 (m, 1H),7.44 (m, 1H), 7.31 (m, 1H), 7.02 (m, 1H), 6.75 (m, 1H), 6.44 (m, 1H),3.81 (m, 2H), 3.02 (m, 2H), 5 1.91 (m, 2H); MS (EI) m/z 288 (M⁺+1), 245.

Example 193-(1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyldihydrochloride from3-(1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl

Yield: 80%. ¹H NMR (CD₃OD) δ 9.01 (m, 2H), 8.42 (m, 1H), 8.28 (m, 1H),7.95 (m, 1H), 7.74 (m, 1H), 7.53 (m, 1H), 7.43 (m, 1H), 7.25 (m, 2H),3.85 (, 2H), 3.06 (s, 2H), 2.28 (m, 2H); MS (EI) m/z 288 (M⁺+1).

Example 203-(5-Fluoro-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyldihydrochloride from3-(5-fluoro-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl

Yield: 80%. ¹H NMR (CD₃OD) δ 8.97 (m, 2H), 8.26 (m, 2H), 7.86 (m, 1H),7.65 (m, 1H), 7.51 (m, 1H), 7.11 (m, 2H), 3.84 (m, 2H), 3.06 (m, 2H),2.28 (m, 2H); MS (EI) m/z 306 (M⁺+1).

Example 213-(6-Fluoro-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 6-fluoroindole-3-carbaldehyde

Yield: 50%. ¹H NMR (CD₃OD) δ 8.67 (m, 2H), 7.97 (m, 1H), 7.66 (m, 1H),7.58 (m, 1H), 7.21 (m, 1H), 7.12 (m, 1H), 6.92 (m, 1H), 6.82 (m, 1H),3.73 (m, 2H), 2.87 (m, 2H), 1.95 (m, 2H); MS (EI) m/z 306 M⁺+1).

Example 223-(7-Methoxy-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 7-methoxyindole-3-carbaldehyde

Yield: 60%. ¹H NMR (CD₃OD) δ 8.67 (m, 2H), 7.98 (m, 1H), 7.58 (m, 2H),6.97 (m, 2H), 6.78 (m, 1H), 6.68 (m, 1H), 3.95 (s, 3H), 3.75 (m, 2H),2.85 (m, 2H), 1.95 (m, 2H); MS (EI) m/z 318 (M⁺+1).

Example 233-(4-Methoxy-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 4-methoxyindole-3-carbaldehyde

Yield: 55%. ¹H NMR (CDCl₃) δ 8.84 (m, 1H), 8.68 (m, 1H), 7.88 (m, 1H),7.70 (m, 1H), 7.37 (m, 2H), 7.13 (m, 1H), 6.98 (m, 1H), 6.49 (m, 1H),3.85 (m, 2H, 3.74 (s, 3H), 2.76 (m, 2H), 1.92 (m, 2H); MS (F) m/z 318(M⁺+1).

Example 243-(5,6-Dihydro-4H-[2,3′]-bipyridinyl-3-ylidenemethyl)-9-methyl-9H-carbazolefrom 9-methyl-9H-carbazole-3-carbaldehyde

Yield: 40%. ¹H NMR (CD₃OD) δ 9.20 (m, 2H), 8.77 (m, 1H), 8.51 (m, 1H),8.24 (m, 1H), 8.15 (m, 1H), 7.85 (m, 1H), 7.63 (m, 4H), 7.32 (m, 1H),3.97 (m, 4H), 3.32 (m, 2H), 5 3.09 (m, 2H), 2.28 (m, 2H); MS (EI) m/z352 (M⁺+1).

Example 253-(6-Methoxy-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 6-methoxyindole-3-carbaldehyde

Yield: 60%. ¹H NMR (DMSO-d₆) δ 8.64 (m, 2H), 7.86 (m, 1H), 7.56 (m, 1H),7.47 (m, 1H), 7.10 (m, 1H), 6.89 (m, 1H), 6.67 (m, 1H), 6.64 (m, 1H),3.74 (s, 3H), 3.68 (m, 2H), 3.74 (s, 3H), 2.71 (m, 2H), 1.77 (m, 2H); MS(EI) m/z 318 (M⁺+1).

Example 263-(1H-Pyrrolo[2,3-b]pyridin-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 1H-pyrrolo[2,3-b]pyridin-3-carbaldehyde

Yield: 35%. ¹H NMR (CD₃OD) δ 8.67 (m, 2H), 8.24 (m, 1H), 7.97 (m, 1H),7.75 (m, 2H), 7.57 (m, 1H), 7.13 (m, 1H), 6.88 (m, 1H), 3.78 (m, 2H),2.88 (m, 2H), 1.94 (m, 2H); MS (EI) m/z 289 (M⁺+1).

Example 273-(1H-Indazol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl from1H-indazol-3-carbaldehyde

Yield: 45%. ¹H NMR (DMS-d₆) δ 8.65 (m, 2H), 7.90 (m, 1H), 7.55 (m, 1H),7.48 (m, 2H), 7.35 (m, 1H), 7.10 (m, 1H), 6.81 (m, 1H), 3.76 (m, 2H),3.13 (m, 2H), 1.75 (m, 2H); MS (EI) m/z 289 (M⁺+1).

Example 283-(3H-Imidazol-4-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl from3H-imidazole-4-carbaldehyde

Yield: 55%. ¹H NMR (CD₃OD) δ 8.77 (m, 1H), 8.72 (m, 1H), 8.02 (m, 1H),7.86 (s, 1H), 7.65 (m, 2H), 6.96 (s, 1H), 3.83 (m, 2H), 3.01 (m, 2H),2.07 (m, 2H); MS (EI) m/z 239 (M⁺+1).

Example 293-(1-Methyl-1H-pyrrol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 1-methyl-1H-pyrrole-3-carbaldehyde

Yield: 40%. ¹H NMR (CD₃OD) δ 8.61 (m, 2H), 7.87 (m, 1H), 7.52 (m, 1H),6.92 (m, 1H), 6.69 (m, 1H), 6.48 (m, 1H), 6.24 (m, 1H), 3.70 (m, 2H),3.67 (s, 3H), 2.79 (m, 2H), 1.90 (m, 2H); MS (EI) m/z 252 (M⁺+1).

Example 303-(5-Fluoro-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 6-fluoroindole-3-carbaldehyde

¹H NMR (CD₃OD) δ 8.68 (m, 2H), 7.98 (m, 1H), 7.73 (s, 1H), 7.60 (m, 1H),7.39 (m, 1H), 6.89 (m, 2H), 3.75 (m, 2H), 2.87 (m, 2H), 1.95 (m, 2H); MS(EI) m/z 306 (M⁺+1).

Example 313-(6-Methyl-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro-[2,3′]bipyridinylfrom 6-methyl-indole-3-carbaldehyde

Yield: 55%. ¹H NMR (CD₃OD) δ 8.68 (m, 2H), 7.98 (m, 1H), 7.60 (m, 2H),7.20 (s, 1H), 7.11 (d, J=6.0 Hz, 1H), 6.89 (s, 1H), 6.86 (m, 1H), 3.76(m, 2H), 2.85 (m, 2H), 2.41 (s, 3H), 1.95 (m, 2H); MS (EI) m/z 302(M⁺+1).

Example 323-(7-Methyl-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 7-methylindole-3-carbaldehyde

Yield: 55%. ¹H NMR (CD₃OD) δ 8.67 (m, 2H), 7.98 (m, 1H), 7.65 (s, 1H),7.59 (m, 1H), 7.06 (m, 1H), 6.95 (m, 3H), 3.77 (m, 2H), 2.88 (m, 2H),2.50 (s, 3H), 1.96 (m, 2H); MS (EI) m/z 302 (M⁺+1).

Example 333-(5-Benzyloxy-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 6-benzyloxyindole-3-carbaldehyde

Yield: 50%. ¹H NMR (CD₃OD) δ 8.70 (m, 2H), 7.95 (m, 1H), 7.61 (m, 2H),7.32 (m, 6H), 6.91 (m, 2H), 6.73 (m, 1H), 5.01 (s, 2H), 3.75 (m, 2H),2.83 (m, 2H), 1.94 (m, 2H); MS (EI) m/z 394 (M⁺+1).

Example 343-(2-Methyl-5-nitro-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro-[2,3′]bipyridinylfrom 2-methyl-6-nitoindole-3-carbaldehyde

Yield: 40%. ¹H NMR (CD₃OD) δ 8.86 (m, 1H), 8.65 (m, 1H), 8.28 (m, 1H),8.04 (m, 2H), 7.56 (m, 1H), 7.42 (m, 1H), 6.73 (s, 1H), 3.91 (m, 2H),2.69 (m, 2H), 1.94 (m, 2H); MS (EI) m/z 347 (M⁺+1).

Example 357-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazinefrom 4-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-7-carbaldehyde

Yield: 62%. ¹H NMR (CDCl₃) δ 8.72-8.61 (m, 2H), 7.80-7.77 (m, 1H),7.32-7.24 (m, 1H), 6.84-6.47 (m, 4H), 4.29-4.24 (m, 2H), 3.84-3.81 (m,2H), 3.33-3.28 (m, 2H), 2.92-2.81 (s, 5H), 1.84-1.78 (m, 2H); MS (EI)m/z 320 (M⁺+1).

Example 363-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)-10-methyl-10H-phenothiazinefrom 10-methyl-10H-phenothiazine-3-carbaldehyde

Yield: 55%. ¹H NMR (CDCl₃) δ 8.72 (m, 1H), 8.64-8.62 (m, 1H), 7.82-7.79(m, 1H), 7.35-7.31 (m, 1H), 7.20-7.09 (m, 4H), 6.94 (t, J=7.4, 1H),6.83-6.76 (m, 2H), 6.51 (s, 1H), 3.86 (t, J=5.5, 2H), 3.38 (s, 3H),2.85-2.80 (m, 2H), 1.87-1.79 (m, 2H); MS (EI) m/z 384 (M⁺+1).

Example 373-[4-(4-Methylpiperazin-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 4-(4-methylpiperazin-1-yl)benzaldehyde

Yield: 28%. ¹H NMR (CDCl₃) δ 8.73-8.61 (m, 2H), 7.80-7.44 (m, 1H),7.32-7.21 (m, 3H), 6.91-6.85 (m, 2H), 6.55 (s, 1H), 3.84-3.81 (m, 2H),3.29-3.25 (m, 4H), 2.85-2.84 (m, 2H), 2.59-2.54 (m, 4H), 2.35 (s, 3H),1.83-1.79 (m, 2H); MS (EI) m/z 347 (M⁺+1).

Example 383-(4-Morpholin-4-benzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl from4-morpholin-4-ylbenzaldehyde

Yield: 55%. ¹H NMR (CDCl₃) δ 8.73-8.62 (m, 2H), 7.35-7.24 (m, 3H),6.89-6.85 (m, 2H), 6.56 (s, 1H), 3.87-3.84 (m, 6H), 3.23-3.19 (m, 4H),2.86-2.84 (m, 2H), 1.85-1.82 (m, 2H); MS (EI) m/z 334 (M⁺+1).

Example 393-(1H-Benzimidazol-5-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 1H-benzimidazole-5-carbaldehyde

Aldehyde Preparation:

The aldehyde was prepared according to: Talaty, C. N.; Zenker, N.;Callery, P. S. J Heterocyclic Chem. 1976, 13, 1121. Data: ¹H NMR(DMSO-d₆) δ 12.89 (bs, 1H), 10.02 (s, 1H), 8.43 (s, 1H), 8.17 (m, 1H),7.73 (m, 2H).

Condensation:

According to representative procedure A. Data: Yield: 45%. ¹H NMR(CDCl₃) δ 8.86-8.85 (m, 1H), 8.77-8.75 (m, 1H), 8.18 (s, 1H), 8.01 (dt,J=8.5, 1.9, 1H), 7.75-7.72 (m, 2H), 7.56-7.52 (m, 1H), 7.35-7.32 (m,1H), 6.92 (s, 1H), 4.00 (t, J=5.5, 2H), 3.06-3.02 (m, 2H), 2.82-2.76 (s,1H), 2.01-1.94 (m, 2H); MS (EI) m/z 289 (M⁺+1).

Example 40[5-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)benzofuran-2-yl]phenylmethanonefrom 2-benzoylbenzofuran-5-carbaldehyde

Yield: 23%. ¹H NMR (CDCl₃) δ 8.78 (d, J=1.3, 1H), 8.66 (m, 1H), 8.05 (d,J=7.1, 1H), 8.04 (d, J=1.4, 1H), 7.86 (dt, J=7.8, 1.9, 1H), 7.68-7.52(m, 6H), 7.42 (dd, 1H, J=8.7, 1.6), 7.36 (dd, 1H, 7.6, 4.9), 6.77 (s,1H), 3.92 (t, J=5.5, 2H), 2.90-2.85 (m, 2H), 1.90-1.82 (m, 2H); MS (EI)m/z 393 (M⁺+1).

Example 416-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)chromen-2-one from2-oxo-2H-chromene-6-carbaldehyde

Yield: 31%. ¹H NMR (CDCl₃) δ 8.76 (d, J=1.6, 1H), 8.66 (dd, J=4.9, 1.6,1H), 7.84 (dt, J=7.8, 1.9, 1H), 7.68 (d, J=9.5, 1H), 7.49-7.32 (m, 4H),6.66 (s, 1H), 6.46 (d, J=9.6, 1H), 3.92 (t, J=5.6, 2H), 2.86-2.81 (m,2H), 1.90-1.82 (m, 2H); MS (EI) m/z 317 (M⁺+1).

Example 425-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)-1,3-dihydrobenzimidazol-2-onefrom 2-oxo-2,3-dihydro-1H-benzimidazole-5-carbaldehyde

Aldehyde Preparation:

The aldehyde was prepared according to: Schmidt, G.; Zeiler, H.-J.;Metzger, K. G. U.S. Pat. No. 4,748,163 (May 31, 1998). Data: ¹H NMR(DMSO-d₆) δ 11.05 (bs, 1H), 10.88 (bs, 1H), 9.78 (s, 1H), 7.63 (d,J=8.2, 1H), 7.36 (s, 1H), 7.01 (d, J=8.2, 1H).

Condensation:

According to representative procedure A. Data: Yield: 37%. ¹H NMR(CDCl₃/CD₃OD) δ 10.67 (bm, 2H), 8.62-8.59 (m, 2H), 7.84 (m, 1H),7.45-7.41 (m, 1H), 6.96-6.92 (m, 3H), 6.54 (s, 1H), 3.72 (t, J=5.3, 2H),2.80-2.77 (m, 2H), 1.75-1.69 (m, 2H); MS (EI) m/z 305 (M⁺+1).

Example 433-(1H-Benztriazol-5-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 1H-benztriazole-5-carbaldehyde

Aldehyde Preparation:

The aldehyde was prepared according to: Schmidt, G.; Zeiler, H.-J.;Metzger, K. G. U.S. Pat. No. 4,748,163 (May 31, 1998). Data: ¹H NMR(DMSO-d₆) δ 10.17 (s, 1H), 8.64 (s, 1H), 8.03 (d, J=8.5, 1H), 7.91 (dd,J=8.4, 1.1, 1H).

Condensation:

According to representative procedure A. Data: Yield: 20%. ¹H NMR(CDCl₃) δ 8.66-8.57 (m, 2H), 7.99-7.83 (m, 3H), 7.58-7.52 (m, 1H),7.50-7.36 (nm 1H), 6.82 (s, 1H), 3.87-3.84 (m, 2H), 2.91-2.86 (m, 2H),1.87-1.80 (m, 2H); MS (EI) m/z 290 (M⁺+1).

Example 443-(2-Morpholin-4-ylbenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl from2-morpholin-4-ylbenzaldehyde

Yield: 14%. ¹H NMR (CDCl₃) δ 8.64 (d, J=1.6, 1H), 8.58 (dd, J=4.9, 1.7,1H), 7.71 (dt, J=7.8, 2.0, 1H), 7.29-7.20 (m, 4H), 7.00 (t, J=7.5, 1H),6.92-6.90 (m, 1H), 6.74 (s, 1H), 3.86 (t, J=5.6, 2H), 3.51 (t, J=4.4,4H), 2.76 (t, J=4.9, 6H), 2.82-2.64 (m, 2H), 1.76-1.72 (m, 2M); MS (EI)m/z 334 (M⁺+1).

Example 453-(1H-Indazol-5-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl from1H-indazole-5-carbaldehyde

Aldehyde Preparation:

The aldehyde was prepared according to: DeLucca, G. V. U.S. Pat. No.6,313,110 B1 (Nov. 6, 2001). Data: ¹H NMR (CDCl₃) δ 9.91 (s, 1H), 8.25(s, 1H), 8.17 (s, 1H), 7.83 (dd, J=8.5, 1.5, 1H), 7.60 (d, J=8.5, 1H).

Condensation:

According to representative procedure A. Data: Yield: 65%. ¹H NMR(CDCl₃) δ 8.80 (d, J=1.7, 2H), 8.68-6.66 (m, 1H), 8.10 (s, 1H),7.90-7.86 (m, 1H), 7.75 (s, 1H), 7.46-7.28 (m, 4H), 6.79 (s, 1H), 3.92(t, J=5.6, 2H), 2.94-2.89 (m, 2H), 1.91-1.83 (m, 2H); MS (EI) m/z 289(M⁺+1).

Example 463-(1H-Indazol-6-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl from1H-indazole-6-carbaldehyde

Aldehyde Preparation:

The aldehyde was prepared according to: DeLucca, G. V. U.S. Pat. No.6,313,110 B1 (Nov. 6, 2001). Data: ¹H NMR (CDCl₃) δ 10.15 (s, 1H), 8.20(s, 1H), 8.05 (m, 1H), 7.91 (d, J=8.8, 1H), 7.70 (dd, J=8.7, 1.6, 1H)

Condensation:

According to representative procedure A. Data: Yield: 62%. ¹H NMR(CDCl₃/CD₃OD) δ 8.81 (m, 1H), 8.73-8.70 (m, 1H), 7.87-7.77 (m, 2H),7.54-7.50 (m, 1H), 7.19-7.16 (m, 1H), 6.88 (s, 1H), 3.98 (t, J=5.5, 2H),3.03-2.98 (m, 2H), 2.10-1.95 (m, 2H); MS (EI) m/z 289 (M⁺+1).

Example 473-(1H-Indazol-4-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl from1H-indazol-4-carboxaldehyde

Aldehyde Preparation:

The aldehyde, 1H-indazol-4-carboxaldehyde, was prepared from3-bromo-2-methylaniline according to the method described for examples45 and 46: Data: ¹H NMR (DMSO-d₆) δ 13.58 (s, 1H), 10.24 (s, 1H); 8.56(s, 1H), 7.97 (d, J=8.5, 1H), 7.85 (dd, J=7.0, 1.0, 1H), 7.62 (dd,J=7.0, 1.5, 1H).

Condensation:

According to representative procedure A. Data: Yield: 76%. ¹H NMR(CDCl₃) δ 8.87 (t, J=1.4, 1H), 8.67 (m, 1H), 7.93 (m, 1H), 7.88 (s, 1H),7.36 (m, 3H), 7.13 (m, 1H), 7.02 (s, 1H) 3.95 (t, J=5.5, 2H), 2.82 (m,2H), 1.83 (m, 2H); MS (EI) m/z 289 (M⁺+1).

Example 483-[2-(4-Methylpiperazin-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 2-(4-methylpiperazin-1-yl)benzaldehyde

Yield: 45%. ¹H NMR (CDCl₃) δ 8.74 (m, 1H), 8.66 (m, 1H), 7.80 (dt,J=7.9, 2.0, 1H), 7.37-7.27 (m, 4H), 7.08-6.98 (m, 2H), 6.81 (s, 1H),3.94 (t, J=5.6, 2H), 2.89-2.81 (m, 6H), 2.27 (s, 3H), 1.89-1.78 (m, 2H);MS (EI) m/z 347 (M⁺+1).

Example 496-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)-3H-benzoxazol-2-onefrom 3-hydroxy-4-nitrobenzaldehyde

5-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)-2-nitrophenol wasprepared by the condensation of anabasine and3-hydroxy-4-nitrobenzaldehyde according to the representative procedureA. Data: ¹H NMR (CDCl₃) δ 8.75 (d, J=1.7, 2H), 8.67 (dd, J=4.9, 1.6,1H), 8.08 (d, J=8.8, 1H), 7.84 (dt, J=7.9, 1.9, 1H), 7.39-7.35 (m, 1H),7.09 (d, J=1.7, 1H), 6.87 (dd, J=8.8, 1.8, 1H), 6.60 (s, 1H), 3.94 (t,J=5.6, 2H), 2.85-2.80 (m, 2H), 1.91-1.83 (m, 2H); MS (EI) m/z 310(M⁺+1). A suspension of the nitrophenol (47.2 mg, 0.153 mmol) and tin IIchloride dihydrate (256 mg, 1.17 mmol, 7.7 eq) in ethanol (3.2 mL) waswarmed to 60° C. 300 μl (0.0161 mmol, 0.11 eq) of a solution of sodiumborohydride, prepared by dissolving 2 mg of the hydride in 1 mL ofethanol, was added over 10 min to the semi-suspension. After 2 h, thereaction mixture was allowed to cool to rt, was diluted with ethylacetate (30 mL) and saturated potassium bicarbonate (30 mL), and wasmaintained for 1 h. The aqueous layer was extracted with ethyl acetate(20 mL) and dichloromethane (2×20 mL) and the combined organic layerswere dried over sodium sulfate. The crude aminophenol (38.6 mg) wasdissolved in dimethylformamide (3.2 mL), was treated withcarbonyldiimidazole (26.9 mg, 0.166 mmol, 1.2 eq) and the reactionmixture was maintained for 16 h. The contents of the reaction werepoured onto ½ saturated brine (50 mL) and extracted with ethyl acetate(2×20 mL) and dichloromethane (2×20 mL) and the combined organic layerswere dried over sodium sulfate. The residue was purified bychromatography [0/1 to 1/3 ethyl acetate/(70/30/1 ethylacetate/methanol/ammonium hydroxide)] to give 24.6 mg (53%) of the titlecompound as an orange solid. Data: ¹H NMR (CDCl₃) δ 8.75 (s, 1H), 8.62(m, 2H), 7.96-7.90 (m, 1H), 7.56-7.49 (m, 1H), 7.30-7.05 (m, 3H),6.65-6.63 (m, 1H), 3.84-3.78 (m, 2H), 2.93-2.84 (m, 2H), 1.92-1.84 (m,2H); MS (EI) m/z 306 (M⁺+1).

Example 503-(4-Pyrrolidin-1-yl-benzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 4-pyrrolidin-1-ylbenzaldehyde

Yield: 44%. ¹H NMR (CD₃Cl) δ 8.74-8.61 (m, 2H), 7.80 (m, 1H), 7.31-7.22(m, 3H), 6.54-6.51 (m, 3H), 3.83-3.81 (m, 2H), 3.31-3.29 (m, 4H),2.87-2.85 (m, 2H), 2.02-1.75 (m, 6H); MS (EI) m/z 318 (M⁺+1).

Example 513-(3-Nitro-4-pyrrolidin-1-ylbenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 3-nitro-4-pyrrolidin-1-ylbenzaldehyde

Yield: 39%. ¹H NMR (CDCl₃) δ 8.73 (dd, J=2.1, 0.7, 1H), 8.64 (dd, J=4.9,1.7, 1H), 7.81 (dt, J_(d)=7.8, J_(t)=2.1, 1H), 7.77 (d, J=2.1, 1H), 7.32(m, 2H), 6.87 (d, J=8.9, 1H), 6.51 (s, 1H), 3.86 (t, J=5.5, 2H), 3.25(m, 4H), 2.85 (m, 2H), 2.00 (m, 5H), 1.85 (m, 2H); MS (EI) m/z 363(M⁺+1).

Example 523-(3-Amino-4-pyrrolidin-1-ylbenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 3-nitro-4-pyrrolidin-1-ylbenzaldehyde

Tin (II) chloride dihydrate (1.32 g, 5.85 mmol, 7.5 eq) was added to asolution of the nitro amine (282 mg, 0.778 mmol) in ethanol (14 mL) andthe slurry was warmed to 60° C. A solution of sodium borohydride inethanol (2 mg/mL, 1.5 mL, 0.079 mmol, 0.1 eq) was added dropwise over 10min to the solution and the reaction mixture was maintained for 2 h at60° C. Upon cooling, the reaction mixture was poured onto saturated,aqueous sodium carbonate (25 mL) and ethyl acetate (25 mL) andmaintained overnight with vigorous stirring. The layers were separatedand the aqueous layer extracted with ethyl acetate (2×25 mL). Thecombined organic layers were dried (sodium sulfate) and concentrated.The residue was purified by chromatography [1/0 to 4/1 to 1/1 ethylacetate/(70/30/1 ethylacetate/methanol/ammonium hydroxide)] to provide102 mg (39%) of the amine as an oil. Data: ¹H NMR (CDCl₃) δ 8.73 (d,J=1.5, 1H), 8.62 (dd, J=4.8, 1.7, 1H), 7.80 (dt, J_(d)=7.8, J_(t)=1.9,1H), 7.31 (ddd, J=8.4, 4.8, 0.7, 1H), 6.92 (d, J=8.1, 1H), 6.72 (m, 2H),6.53 (s, 1H), 3.85 (t, J=5.5, 2H), 3.82 (bs, 1H), 3.09 (m, 4H), 2.86 (m,2H), 1.93 (m, 4H), 1.83 (m, 2H); MS (EI) m/z 333 (M⁺+1).

Example 533-(3-Amino-4-piperidin-1-ylbenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 3-nitro-4-piperidin-1-ylbenzaldehyde

Yield: 51%. ¹H NMR (CDCl₃) δ 8.73 (t, J=1.5, 1H), 8.62 (dd, J=4.9, 1.7,1H), 7.80 (dt, J_(d)=7.8, J_(t)=1.9, 1H), 7.31 (ddd, J=7.8, 4.9, 0.8,1H), 6.94 (d, J=8.0, 1H) 6.71 (m, 2H), 6.53 (s, 1H), 3.94 (bs, 1H), 3.85(t, J=5.5, 2H), 2.86 (m, 6H), 1.82 (m, 2H), 1.70 (m, 5H), 1.59 (m, 2H);MS (EI) m/z 347 (M⁺+1).

Example 543-(3-Amino-4-morpholin-4-ylbenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 3-nitro-4-morpholin-4-ylbenzaldehyde

Yield: 68%. ¹H NMR (CDCl₃) δ 8.73 (s, 1H), 8.63 (d, J=3.7, 1H), 7.81(dt, J_(d)=7.8, J_(t)=1.9, 1H), 7.32 (dd, J=7.5, 4.9, 1H), 6.96 (d,J=8.1, 1H), 6.72 (m, 2H), 6.54 (s, 1H), 3.95 (bs, 2H), 3.86 (m, 6H),2.93 (m, 4H), 2.85 (m, 2H), 1.82 (m, 2H); MS (EI) m/z 348 (M⁺+1).

Example 553-(5-Chloro-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylDihydrochloride from 5-chloro-1H-indol-3-carboxaldehyde

¹H NMR (DMSO-d₆) δ 8.96 (d, J=4.8, 1H), 8.92 (s, 1H), 8.36 (m, 1H), 8.22(m, 1H), 7.81 (m, 1H), 7.59 (m, 1H), 7.54 (m, 2H), 7.24 (m, 1H), 3.78(m, 2H), 2.91 (m, 2H), 2.10 (m, 2H); MS (EI) m/z 322 (M⁺+1).

Example 563-(3-Piperidin-1-ylbenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl from3-piperidin-1-ylbenzaldehyde

Yield: 44%. ¹H NMR (CDCl₃) δ8.75 (t, J=1.4, 1H), 8.64 (dd, J=4.9, 1.7,1H), 7.85 (dt, J_(d)=7.8, J_(t)=2.1, 1H), 7.29 (m, 3H), 6.88 (m, 1H),6.74 (m, 2H), 6.65 (s, 1H), 3.88 (m, 2H), 3.14 (m, 3H), 2.85 (m, 2H),1.84 (m, 2H), 1.67 (m, 3H), 1.61 (m, 3H); MS (EI) m/z 332 (M⁺+1).

Example 573-(Benzothiazol-5-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl frombenzothiazol-5-carboxaldehyde

Aldehyde Preparation:

To a solution of 4-chloro-3-nitrobenzoic acid (20 g, 99.2 mmol, 1.0 eq)in dimethylformamide (400 mL) was added potassium carbonate (35 g, 254mmol, 2.55 eq). The mixture was stirred 30 min and ethyl iodide (18.6 g,119 mmol, 1.20 eq) was added. The reaction mixture was stirred at 50° C.for 4 h. Water (3 L) was added and the mixture was extracted withdiethyl ether (2×500 mL). The organic extracts were combined, washedwith brine (1 L), dried over anhydrous sodium sulfate and concentrated.The residue was crystallized from hexanes to provide 19.7 g (86%) of theester. Data: ¹H NMR (500 MHz, CDCl₃) δ 8.51 (d, 1H), 8.17 (dd, 1H), 7.65(d, 1H), 4.43 (q, 2H), 1.42 (t, 3H). Sulfur (1.60 g, 49.9 mmol, 0.58 eq)was dissolved in a solution of sodium sulfide nonahydrate (12.0 g, 50.0mmol, 0.58 eq) in water (60 mL). This solution was combined with asolution of ethyl 4-chloro-3-nitrobenzoate (19.6 g, 85.4 mmol, 1.00 eq)in ethanol (100 mL). The resulting mixture was heated at reflux for 3 h.The hot reaction mixture was poured into water (600 mL) and stirred for15 min. The product was isolated by filtration and recrystallized fromethanol to provide 16.45 g (77%) of the disulfide. Data: ¹H NMR (500MHz, CDCl₃) δ 8.96 (d, 1H), 8.19 (dd, 1H), 7.88 (d, 1H), 4.43 (q, 2H),1.41 (t, 3H). A mixture of diethyl 4,4′-dithiobis(3-nitrobenzoate) (11.2g, 24.75 mmol, 1.00 eq) and zinc granules (15.0 g, 234 mmol, 9.47 eq) informic acid (600 mL) was heated to reflux for 48 h. The mixture wascooled to room temperature and concentrated to dryness on vacuum rotaryevaporator. The residue was partitioned between ethyl acetate (500 mL)and saturated aqueous sodium bicarbonate (500 mL). The organic layer wasseparated, dried over anhydrous sodium sulfate and concentrated onvacuum rotary evaporator. The residue was purified by chromatography onneutral Alumina (1/0 to 0/1 hexanes/dichloromethane) to provide 5.30 g(51%) of the benzthiazole ester. Data: ¹H NMR (500 MHz, CDCl₃) δ 9.08(s, 1H), 8.83 (d, 1H), 8.14 (dd, 1H), 8.02 (d, 1H), 4.45 (q, 2H), 1.44(t, 3H); MS (EI) m/z 208 (M⁺+1). Diisobutylaluminum hydride (1.0 M indichloromethane, 6.0 mL, 6 mmol, 1.05 eq) was added over 15 min to asolution of the ester (1.18 g, 5.70 mmol) in dichloromethane (40 mL) at−35° C. The reaction mixture was allowed to warm to rt and wasmaintained overnight. Analysis of the reaction progress by thin layerchromatography revealed the presence of starting material. The reactionmixture was cooled to 0° C. and was treated with additionaldiisobutylaluminum hydride (6.0 mL, 6 mmol). After 4 h at rt, thereaction was quenched by the addition of water (10 mL) and the slurrywas poured onto 5% sodium hydroxide and dichloromethane (200 mL) andmaintained for 30 min with vigorous stirring. The organic layer wasseparated, washed with brine, dried (sodium sulfate), and concentrated.The residue was dissolved in dichloromethane (100 mL) and was treatedwith manganese (IV) oxide (3.0 g) and powdered 4 Å sieves (3.0 g). Thereaction mixture was filtered through Celite (100 mL dichloromethanerinse) after 14 h and the filtrate was extracted with 0.6 N aqueoussodium hydrogen sulite (2×150 mL). The combined aqueous layers wereback-extracted with dichloromethane (50 mL), were made basic (pH 11) bythe addition of 50% sodium hydroxide, and were extracted with ethylacetate (2×100 mL). The ethyl acetate layers were dried (sodium sulfate)and concentrated to provide 268 mg (29%) of the aldehyde as a tan solid.Data: ¹H NMR (CDCl₃) δ 10.18 (s, 1H), 9.13 (s, 1H), 8.61 (d, J=1.0, 1H),8.11 (d, J=8.0, 1H), 8.01 (dd, J=8.5, 1.5, 1H).

Condensation:

According to procedure A. Data: Yield: 86%. ¹H NMR (CD₃OD) δ 8.97 (s,1H), 8.75 (s, 1H), 8.60 (s, 1H), 8.06 (d, J=0.6, 1H), 7.87 (d, J=8.4,1H), 7.82 (dt, J_(d)=7.8, J_(t)=1.8, 1H), 7.30 (dd, J=7.8, 4.8, 1H),7.26 (dd, J=8.4, 1.6, 1H), 6.76 (s, 1H), 3.86 (t, J=5.5, 2H), 2.85 (m,2H), 1.79 (m, 2H); MS (EI) m/z 306 (M⁺+1).

Example 583-(Benzothiazol-6-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl fromBenzothiazol-6-carboxaldehyde

Aldehyde Preparation:

According to preparation detailed in example 57 from3-chloro-4-nitrobenzoic acid. Data: ¹H NMR (CDCl₃) δ 10.16 (s, 1H), 9.22(s, 1H), 8.52 (d, J=1.5, 1H), 8.27 (d, J=8.5, 1H), 8.05 (dd, J=8.5, 1.5,1H).

Condensation:

According to procedure A. Data: Yield: 63%. ¹H NMR (CDCl₃) δ 9.02 (s,1H), 8.78 (bs, 1H), 8.65 (bs, 1H), 8.10 (d, J=8.5, 1H), 7.91 (s, 1H),7.86 (dt, J_(d)=7.8, J_(t)=1.9, 1H), 7.44 (dd, J=8.6, 1.5, 1H), 7.36(dd, J=7.7, 4.8, 1H), 6.79 (s, 1H), 3.92 (t, J=5.7, 2H), 2.89 (m, 2H),1.90 (m, 2H); MS (ED m/z 306 (M⁺+1).

Example 593-(3,4-Dihydro-2H-benzo[1,4]oxazin-7-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 3,4-dihydro-2H-benzo[1,4]oxazin-7-carboxaldehyde

Aldehyde Preparation:

The phenol, 5-[1,3]dioxan-2-yl-2-nitrophenol, used as a startingmaterial was prepared from 4-nitro-3-hydroxybenzaldehyde according to:Belliotti, T. R.; Wustrow, D. J.; Brink, W. A.; Zoski, K. T.; Shih,Y.-H.; Whetzel, S. Z.; Georgic, L. M.; Corbin, A. E.; Akunne, H. C.;Heffner, T. G.; Pugsley, T. A.; Wise, L. D. J. Med. Chem. 1999, 42,5181. To a solution of the phenol (2.55 g, 11.3 mmol) indimethylformamide (20 mL) was added potassium carbonate (2.56 g, 18.5mmol, 1.6 eq) and ethyl bromoacetate (1.5 mL, 14 mmol, 1.2 eq). Thereaction mixture was maintained for 18 h at rt and was poured onto ½saturated brine and extracted with ethyl acetate (3×60 mL). The combinedorganic layers were washed with water and brine, were dried over sodiumsulfate, and were concentrated to provide(5-[1,3]dioxan-2-yl-2-nitrophenoxy)acetic acid ethyl ester as a goldoil. The ester was dissolved in ethanol (63 mL) and was treated with asolution of calcium chloride (1.42 g, 9.66 mmol) in water (19 mL) andwith zinc dust (11.0 g, 16.8 mmol). The grey suspension was heated at100° C. for 3 h and was filtered (hot) through Celite (ethyl acetatewash). The filtrate was concentrated to approximately 25 mL and theslurry was transferred to a separatory funnel containing ethyl acetate(200 mL). The organic layer was separated and concentrated to provide2.19 g of 6-[1,3]dioxan-2-yl-3,4-dihydro-1H-quinolin-2-one as an oilthat solidified upon standing. The amide (2.19 g, 9.31 mmol) was addedin portions to a suspension of lithium aluminum hydride (576 mg, 14.2mmol, 1.5 eq) in tetrahydrofuran (50 mL) over 15 min. The reactionmixture was maintained for 3 h at rt and was quenched with a saturated,aqueous solution of sodium potassium tartrate (10 mL). The resultantslurry was maintained overnight and was diluted with water (40 mL) andextracted with dichloromethane (3×30 mL). The combined organic layerswere dried over sodium sulfate, concentrated, and the residue waspurified by chromatography (1/1 hexane/ethyl acetate) to provide 1.17 g(57%) of 6-[1,3]dioxan-2-yl-1,2,3,4-tetrahydroquinoline as a 10/1mixture of the acetal/aldehyde. This amine served as a starting materialfor examples 59, 61, and 62. A portion of the mixture (144 mg) wasdissolved in dichloromethane (5 mL), diluted with 1 N hydrochloric acid(5 mL), and was maintained for 14 h with vigorous stirring. The reactionwas neutralized with solid sodium carbonate, extracted withdichloromethane (3×10 mL), and the combined organic layers were driedover sodium sulfate and concentrated. The residue was purified bychromatography (4/1 to 2/1 hexane/ethyl acetate) to provide 87.1 mg(82%) of the aldehyde as a solid Data: ¹H NMR (CDCl₃) δ 9.61 (s, 1H),7.24 (m, 2H), 6.60 (d, J=8.8, 1H), 4.39 (bs, 1H), 4.17 (t, J=4.3, 2H),3.44 (t, J=4.4, 2H).

Condensation:

According to procedure A. Data: Yield: 85%. ¹H NMR (CDCl₃) δ 8.72 (s,1H), 8.62 (s, 1H), 7.80 (dt, J_(d)=7.8, J_(t)=1.8, 1H), 7.31 (dd, J=7.5,4.7, 1H), 6.84 (d, J=1.9, 1H), 6.72 (dd, J=8.2, 1.8, 1H), 6.53 (d,J=8.2, 1H), 6.48 (s, 1H), 4.24 (m, 2H), 3.83 (m, 2H), 3.44 (m, 2H), 2.85(m, 2H), 1.82 (m, 2H); MS (EI) m/z 306 (M⁺+1).

Example 603-(3,4-Dihydro-2H-benzo[1,4]oxazin-7-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylTrihydrochloride from 3,4-dihydro-2H-benzo[1,4]oxazin-7-carboxaldehyde

Yield: 75%. ¹H NMR (CD₃OD) δ 9.28 (s, 1H), 9.18 (d, J=5.5, 1H); 8.87 (d,J=8.0, 1H), 8.35 (dd, J=8.0, 6.0, 1H), 7.23 (d, J=9.0, 1H), 7.18 (d,J=12, 2H), 6.76 (d, J=8.5, 1H), 5.50 (s, 1H), 4.21 (t, J=5.5, 2H), 3.87(t, J=6.0, 2H), 3.54 (m, 2H), 3.11 (m, 2H), 2.21 (m, 2H); MS (EI) m/z306 (M⁺+1).

Example 613-(4-Cyclopropylmethyl-3,4-dihydro-2H-benzo[1,4]oxazin-7-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 3,4-dihydro-2H-benzo[1,4]oxazin-7-carboxaldehyde

Aldehyde Preparation:

The amine from example 59 (338 mg, 1.53 mmol) was dissolved indichloromethane (3.0 mL) and was treated with pyridine (0.19 mL, 2.3mmol, 1.5 eq) and cyclopropylcarbonyl chloride (0.17 mL, 1.9 mmol, 1.2eq). After 3 h, the contents of the reaction were adsorbed onto a bed ofsilica gel and were purified by chromatography (1/1 hexane/ethylacetate) to provide 481 mg of the tertiary amide. The amide (442 mg) wasdissolved in tetrahydrofuran (8 mL) and was treated with lithiumaluminum hydride (88.1 mg, 2.21 mmol). The reaction was quenched after 3h with a saturated, aqueous solution of sodium potassium tartrate (10mL) and the resultant slurry was extracted with dichloromethane (3×30mL). The residue was dissolved in tetrahydrofuran (3 mL) and was dilutedwith 1 N hydrochloric acid (1 mL). After 6 h, the reaction mixture wasneutralized with saturated potassium carbonate and extracted withdichloromethane (3×30 mL) and the combined organic layers were driedover sodium sulfate. The residue was purified by chromatography (3/7hexane/ethyl acetate) to give 31.5 mg of the aldehyde as an inseparablemixture (2/1) of amine/amide. Data: ¹H NMR (CDCl₃) δ 9.68 (s, 1H), 7.31(m, 1H), 6.72 (m, 2H), 4.24 (m, 2H), 3.45 (m, 2H), 3.11 (m, 2H), 1.04(m, 1H), 0.56 (m, 2H), 0.23 (m, 2H).

Condensation:

According to procedure A. Data: Yield: 19%. ¹H NMR (CDCl₃) δ 8.72 (s,1H), 8.61 (s, 1H), 7.79 (m, 1H), 7.29 (m, 1H), 6.77 (m, 3H), 6.48 (s,1H), 4.24 (s, 2H), 3.82 (s, 2H), 3.46 (s, 2H), 3.16 (d, J=5.2, 2H), 2.86(bs, 2H), 1.82 (bs, 2H), 1.26 (m, 1H), 0.56 (m, 2H), 0.21 (m, 2H); MS(EI) m/z 360 (M⁺+1).

Example 623-(4-Ethyl-3,4-dihydro-2H-benzo[1,4]oxazin-7-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 3,4-dihydro-2H-benzo[1,4]oxazin-7-carboxaldehyde

Aldehyde Preparation:

The amine from example 59 (160 mg, 0.723 mmol) was dissolved intetrahydrofuran (4.5 mL) and was treated with sodium hydride (36 mg, 1.5mmol). After 30 min, the reaction mixture was treated with iodoethane(0.15 mL, 1.9 mmol). The reaction was quenched with a water (10 mL) andthe resultant slurry was extracted with dichloromethane (3×30 mL). Theresidue was dissolved in tetrahydrofuran (3 mL) and was diluted with 1 Nhydrochloric acid (1 mL). After 2 h, the reaction mixture wasneutralized with saturated potassium carbonate and extracted withdichloromethane (3×30 mL) and the combined organic layers were driedover sodium sulfate. The residue was purified by chromatography (3/7hexane/ethyl acetate) to give 35.0 mg of the aldehyde. Data: ¹H NMR(CDCl₃) δ 9.67 (s, 1H), 7.37 (dd, J=8.4, 1.9, 1H), 7.27 (d, J=1.8, 1H),6.69 (d, J=8.4, 1H), 4.22 (t, J=4.4, 2H), 3.44 (m, 4H), 1.20 (t, J=7.1,3H).

Condensation:

According to procedure A. Data: Yield: 86%. ¹H NMR (CDCl₃) δ 8.73 (s,1H), 8.61 (s, 1H), 7.80 (dt, J_(d)=7.8, J_(t)=1.9, 1H), 7.30 (dd, J=7.6,4.8, 1H), 7.20 (m, 1H), 6.86 (d, J=2.0, 1H), 6.80 (dd, J=8.5, 2.0, 1H),6.62 (d, J=8.4, 1H), 6.48 (s, 1H), 4.17 (m, 2H), 3.82 (t, J=5.4, 2H),3.37 (m, 4H), 2.86 (m, 2H), 1.88 (m, 2H), 1.15 (t, J=7.0, 3H); MS (EI)m/z 334 (M⁺+1).

Example 633-(1-Phenyl-1H-pyrrol-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 1-phenyl-1H-pyrrol-2-carboxaldehyde

Yield: 6%. MS (EI) m/z 314 (M⁺+1).

Example 643-[2-5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)pyrrol-1-yl]benzonitrilefrom 1-(3-cyanophenyl)-1H-pyrrol-2-carboxaldehyde

Yield: 22%. ¹H NMR (CDCl₃) δ 8.50-8.48 (m, 1H), 8.43 (d, J=1.6, 1H),7.76 (d, J=7.9, 1H), 7.69 (d, J=7.8, 1H), 7.58-7.54 (m, 2H), 7.49-7.48(m, 1H), 7.42-7.40 (m, 1H), 7.12-7.11 (m, 1H), 6.79-6.78 (m, 1H), 6.45(t, J=3.4, 1H), 6.18 (s, 1H), 3.77-3.73 (m, 2H), 2.87-2.83 (m, 2M), 1.93(m, 2H); MS (EI) m/z 339 (M⁺+1).

Example 653-(2-Cyclohexylmethyl-2H-pyrazol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 2-cyclohexylmethyl-2H-pyrazole-3-carbaldehyde

Aldehyde Preparation:

To a solution of pyrazole (1.00 g, 14.7 mmol) in of dimethylformamide(10=L) was added sodium hydride (60% oil dispersion, 450 mg, 11 mmol).After 5 min bromomethylcyclohexane (2.4 mL, 17 mmol) was added bysyringe and the mixture was maintained overnight. The reaction mixturewas quenched with methanol, diluted with water, and extracted with ether(2×). The combined organic layers were dried over magnesium sulfate andconcentrated in vacuo. The residue was purified by chromatography (95/5hexanes/ethyl acetate) to provide 500 mg (27%) of1-cyclohexylmethyl-1H-pyrazole. To a solution of1-cyclohexylmethyl-1H-pyrazole (490 mg, 3.00 mmol) in tetrahydrofuran(10 mL) at −78° C. was added a 2.5 M solution of n-butyllithium inhexanes (1.5 mL, 3.8 mmol). The reaction mixture was maintained at −78°C. for 1 h and was treated with dimethylformamide (1.0 mL, 13 mmol). Thereaction mixture was allowed to warm to rt, maintained overnight, andwas quenched with methanol. The reaction mixture was diluted with waterand was extracted with ether (2 x). The combined organic layers weredied over magnesium sulfate and concentrated in vacuo. The residue waspurified by chromatography (95/5 hexanes/ethyl acetate) to provide 390mg (68%) of 2-cyclohexylmethyl-2H-pyrazole-3-carbaldehyde.

Condensation:

According to procedure A. Data: Yield: 34%. ¹H NMR (CDCl₃) δ 8.75 (d,J=1.4; 1H), 8.68-8.66 (m, 1H), 7.83-7.79 (m, 1H), 7.51 (d, J=1.6, 1H),7.38-7.27 (m, 1H), 6.47-6.44 (m, 1H), 3.88 (t, J=5.6, 2H), 3.75 (d,J=7.2, 2H), 2.80-2.75 (m, 2H), 1.91-1.83 (m, 2H), 1.64-1.58 (m, 4H),1.41-1.37 (m, 2H), 1.16-1.06 (m, 3H), 0.84-0.76 (m, 2H); MS (EI) m/z 335(M⁺+1).

Example 663-(2-Cyclopentyl-2H-pyrazol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 2-cyclopentyl-2H-pyrazole-3-carbaldehyde

Aldehyde Preparation:

The aldehyde was prepared in a manner analogous to example 65.

Condensation:

According to representative procedure A. Data: Yield: 5%. MS (EI) m/z307 (M⁺+1).

Example 673-[1-(4-Chlorophenyl)-1H-Pyrrol-2-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 1-(4-Chlorophenyl)-1H-pyrrol-2-carboxaldehyde

Yield: 2%. ¹H NMR (MeOD) δ 8.50-8.48 (m, 1H), 8.44-8.43 (m, 1H),7.73-7.70 (m, 1H), 7.39-7.33 (m, 3H), 7.15-7.10 (m, 2H), 7.07-7.06 (m,1H), 6.76 (d, J=3.8, 1H), 6.43-6.41 (m, 1H), 6.18 (s, 1H), 3.76-3.72 (m,2H), 2.87-2.82 (m, 2H), 1.95-1.86 (m, 2H); MS (EI) m/z 349 (M⁺+1).

Example 683-[1-(4-Trifluoromethoxyphenyl)-1H-pyrrol-2-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 1-(4-trifluoromethoxy-phenyl)-1H-pyrrole-2-carbaldehyde

Yield: 6%. ¹H NMR (CDCl₃) δ 8.45-8.43 (m, 2H), 7.76-7.72 (m, 1H),7.36-7.24 (m, 5H), 7.11-7.09 (r, 1H), 6.79 (d, J=3.2, 1H), 6.45-6.43 (m,1H), 6.21 (s, 1H), 3.77-3.73 (m, 2H), 2.89-2.84 (m, 2H), 1.94-1.88 (m,2H); MS (EI) m/z 398 (M⁺+1).

Representative Procedure B: Example 693-(4-Piperazin-1-ylbenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl from3-(4-iodobenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl

3-(4-Iodobenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl was preparedfrom anabaseine and 4-iodobenzaldehyde according to representativeprocedure A. Data: ¹H NMR (CDCl₃) δ 8.61 (m, 2H), 7.92 (dd, J=7.2, 0.4,1H), 7.73 (dd, J=8.8, 2, 2H), 7.52 (m, 1H), 7.12 (d, J=8.4, 2H), 6.56(s, 1H), 3.82 (t, J=5.6, 2H), 2.84 (m, 2H), 1.85 (m, 2H); MS (EI) m/z375 (M⁺+1). In four 5 mL microwave reaction vessels was added the iodide(1.23 g, 3.29 mmol), 1-Boc-piperazine (835 mg, 4.48 mmol, 1.4 eq),tris(dibenzylideneacetone)dipalladium (0) (302 mg, 0.330 mmol, 0.1 eq),tri-tert-butylphosphine tetrafluoroborate (238 mg, 0.820 mmol, 0.25 eq),and sodium tert-butoxide (557 mg, 5.80 mmol, 1.8 eq). The vessel wasevacuated, back-filled with argon gas, and the contents diluted withtoluene (20 mL). The vessel was sealed and subjected to microwaveirradiation at 160° C. for 300 s. The contents of the reaction werediluted with ethyl acetate (20 mL), were filtered through Celite (ethylacetate wash), and were concentrated. The residue was purified bychromatography [1/0 to 4/1 ethyl acetate/(70/30/1ethylacetate/methanol/ammonium hydroxide)] to provide a red oil. The oilwas diluted with dichloromethane (10 mL) and treated withtrifluoroacetic acid (5 mL). After 2 h, the contents of the reactionwere added to a SCX column and was washed with methanol (50 mL). Theproduct was eluted with 2 M ammonia in methanol to give 765 mg (70%) ofthe piperidine adduct as an oil. Data: ¹H NMR (CD₃OD) δ 8.62 (broad s,2H), 7.91 (m, 1H), 7.54 (m, 1H), 7.33 (d, J=8.8, 2H), 7.01 (d, J=8.9,2H), 6.59 (s, 1H), 3.79 (m, 2H), 3.43 (m, 3H), 3.25 (m, 4H), 2.92 (m,2H), 1.89 (m, 2H); MS (EI) m/z 333 (M⁺+1).

Using this general procedure the following compounds were prepared:

Example 703-[4-(trans-2,5-Dimethylpiperazin-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 3-(4-iodobenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl

Yield: 24%. ¹H NMR (CD₃OD) δ 8.61 (m, 2H), 7.91 (m, 1H), 7.53 (m, 1H),7.31 (d, J=8.6, 2H), 7.11 (d, J=8.6, 2H), 6.57 (s, 1H), 3.80 (t, J=5.5,2H), 3.11 (m, 4H), 2.89 (m, 2H), 2.61 (m, 2H), 1.57 (m, 2H), 1.09 (d,J=6.4, 3H), 0.94 (d, J=6.1, 3H); MS (EI) m/z 361 (M⁺+1).

Example 713-[4-(cis-3,5-Dimethylpiperazin-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 3-(4-iodobenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl

Yield: 76%. ¹H NMR (CD₃OD) δ 8.60 (m, 2H), 7.89 (d, J=7.8, 1H), 7.52(dd, J=7.8, 4.9, 1H), 7.27 (d, J=8.7, 2H), 6.95 (d, J=8.8, 2H), 6.51 (s,1H), 3.77 (t, J=5.4, 1H), 3.69 (d, J=12.4, 2H), 2.98 (m, 2H), 2.90 (m,2H), 2.33 (t, J=11.9, 2H), 1.86 (m, 2H), 1.16 (d, J=6.4, 6H); MS (EI)m/z 361 (M⁺+1).

Example 723-(4-Thiomorpholin-4-ylbenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 3-(4-iodobenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl

Yield: 91%. ¹H NMR (CD₃OD) δ 8.61 (m, 2H), 7.90 (dt, J_(d)=7.9, J=1.8,1H), 7.53 (ddd, J=7.8, 5.0, 0.8, 1H), 7.28 (d, J=8.9, 2H), 6.90 (d,J=9.0, 2H), 6.54 (s, 1H), 3.77 (t, J=5.4, 2H), 3.66 (m, 4H), 2.91 (m,2H), 2.65 (m, 4H), 1.88 (m, 2H); MS (EI) m/z 350 (M⁺+1).

Example 733-[4-(1-Oxo-1λ4-thiomorpholin-4-yl)-benzylidene]-3,4,5,6-tetrahydro-[2,3′]bipyridinylfrom3-(4-thiomorpholin-4-ylbenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl

To a solution of the thio ether from example 72 (42.8 mg, 0.122 mmol) indichloromethane (1 mL) was added m-chloroperoxybenzoic acid (63.0 mg,0.281 mmol, 2.3 eq) After 15 h, the reaction mixture was poured ontosaturated sodium bicarbonate (3 mL) and was extracted withdichloromethane (3×10 mL) and dried over sodium sulfate. The residue waspurified by chromatography [3/7 ethyl acetate/(70/30/1ethylacetate/methanol/ammonium hydroxide)] to provide 22.1 mg (49%) ofthe sulfoxide.

¹H NMR (CD₃OD) δ 8.73 (m, 1H), 8.63 (m, 1H), 7.82 (dt, J_(d)=7.8,J_(t)=1.9, 1H), 7.33 (dd, J=7.5, 4.8, 1H), 7.27 (d, J=8.8, 2H), 6.91 (d,J=8.9, 2H), 6.56 (s, 1H), 4.07 (m, 2H), 3.86 (t, J=5.5, 2H), 3.67 (m,2H), 2.84 (m, 6H), 1.84 (m, 2H); MS (EI) m/z 366 (M⁺+1).

Example 743-[4-(1,1-Dioxo-1λ6-thiomorpholin-4-yl)-benzylidene]-3,4,5,6-tetrahydro-[2,3′]bipyridinylfrom3-(4-thiomorpholin-4-ylbenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl

To a solution of the thio ether from example 72 (43.5 mg, 0.122 mmol) indichloromethane (1 mL) was added m-chloroperoxybenzoic acid (136 mg,0.607 mmol, 4.9 eq) After 16 h, the reaction mixture was poured ontosaturated sodium bicarbonate (3 mL) and was extracted withdichloromethane (3×10 mL) and dried over sodium sulfate. The residue waspurified by chromatography [3/7 ethyl acetate/(70/30/1ethylacetate/methanol/ammonium hydroxide)] to provide 2.1 mg (4%) of thesulfone.

¹H NMR (CDCl₃) δ 8.74 (s, 1H), 8.63 (m, 1H), 7.84 (m, 1H), 7.34 (dd,J=7.8, 5.0, 1H), 7.28 (d, J=9.5, 2H), 6.91 (d, J=8.9, 2H), 6.57 (s, 1H),4.08 (m, 2H), 3.86 (m, 3H), 3.67 (m, 2H), 2.78 (m, 5H), 1.85 (m, 2H); MS(EI) m/z 382 (M⁺+1).

Example 753-[4-(2,6-Dimethylmorpholin-4-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 3-(4-iodobenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl

Yield: 96%. ¹H NMR (CD₃OD) δ 8.62 (m, 2H), 7.90 (dt, J_(d)=7.8,J_(t)=1.8, 1H), 7.54 (dd, J=7.8, 5.0, 1H), 7.29 (d, J=8.8, 2H), 6.94 (d,J=9.1, 2H), 6.89 (s, 1H), 3.77 (m, 2H), 3.67 (m, 3H), 3.34 (m, 2H), 2.95(m, 2H), 2.35 (m, 1H), 1.90 (m, 2H), 1.24 (m, 6H); MS (EI) m/z 362(M⁺+1).

Example 763-(4-[1,4]Diazepan-1-ylbenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 3-(4-iodobenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl

Yield: 69%. ¹H NMR (CD₃OD) δ 8.61 (dd, J=4.9, 1.5, 1H), 8.57 (d, J=1.5,1H), 7.88 (dt, J_(d)=7.8, J_(t)=1.8, 1H), 7.51 (ddd, J=7.8, 4.9, 0.6,1H), 7.26 (d, J=8.9, 2H), 6.77 (d, J=9.0, 2H), 6.50 (s, 1H), 3.68 (m,6H), 3.13 (m, 2H), 2.93 (m, 4H), 2.04 (m, 2H), 1.89 (m, 3H); MS (EI) m/z347 (M⁺+1).

Example 773-[3-(trans-2,5-Dimethylpiperazin-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 3-(3-iodobenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl

Yield: 24%. ¹H NMR (CD₃OD) δ 8.63 (bs, 2H), 7.94 (m, 1H), 7.54 (dd,J=7.6, 4.9, 1H), 7.38 (t, J=7.8, 1H), 7.16 (m, 3H), 6.63 (s, 1H), 3.83(m, 2H), 3.35 (m, 2H), 3.20 (m, 2H), 2.87 (m, 4H), 1.86 (m, 2H), 1.28(m, 3H), 1.19 (m, 3H), 0.94 (m, 3H); MS (EI) m/z 361 (M⁺+1).

Example 783-[3-(cis-3,5-Dimethylpiperazin-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 3-(3-iodobenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl

Yield: 29%. ¹H NMR (CD₃OD) δ 8.62 (m, 2H); 7.95 (m, 1H), 7.54 (dd,J=7.8, 4.9, 1H), 7.31 (t, J=7.9, 1H), 6.96 (m, 3H), 6.63 (s, 1H), 3.80(m, 3H), 3.38 (m, 4H), 2.86 (m, 2H), 2.63 (dd, J=13, 11, 2H), 1.86 (m,2H), 1.34 (d, J=6.5, 6H); MS (EI) m/z 361 (M⁺+1).

Example 793-(3-Thiomorpholin-4-yl-benzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 3-(3-iodobenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl

Yield: 54%. ¹H NMR (CD₃OD) δ 8.63 (m, 2H), 7.94 (dt, J_(d)=7.9,J_(t)=1.7, 1H), 7.54 (ddd, J=7.8, 5.0, 0.8, 1H), 7.29 (m, 1H), 7.26 (t,J=8.1, 1H), 6.88 (m, 3H), 6.64 (s, 1H), 3.83 (t, J=5.4, 2H), 3.51 (m,4H), 2.89 (m, 3H), 2.70 (m, 4H), 1.90 (m, 2H); MS (EI) m/z 350 (M⁺+1).

Example 803-[3-(2,6-Dimethylmorpholin-4-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 3-(3-iodobenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl

Yield: 83%. ¹H NMR (CD₃OD) δ 8.63 (m, 2H), 7.94 (dt, J_(d)=7.8,J_(t)=1.8, 1H), 7.54 (ddd, J=7.8, 4.9, 0.6, 1H), 7.30 (m, 2H), 6.90 (m,3H), 6.63 (s, 1H), 3.78 (m, 3H), 3.50 (m, 3H), 3.31 (m, 1H), 2.88 (m,2H), 2.29 (t, J=1.8, 1H), 1.86 (m, 2H), 1.27 and 1.20 (two d, J=6.4 ea,6H); MS (EI) m/z 362 (M⁺+1).

Example 813-(3-[1,4]Diazepan-1-ylbenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 3-(3-iodobenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl

Yield: 48%. ¹H NMR (CD₃OD) δ 8.61 (m, 2H), 7.92 (dt, J_(d)=7.8,J_(t)=1.8, 1H), 7.52 (dd, J=7.2, 4.3, 1H), 7.23 (t, J=8.0, 1H), 6.73 (m,3H), 6.61 (s, 1H), 3.81 (m, 2H), 3.69 (m, 2H), 3.57 (m, 2H), 3.20 (m,2H), 3.05 (m, 2H), 2.88 (m, 2H), 2.07 (m, 2H), 1.88 (m, 2H); MS (EI) m/z347 (M⁺+1).

Example 823-[3-(4-Phenylpiperazin-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 3-(3-iodobenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl

Yield: 55%. ¹H NMR (CD₃OD) δ 8.63 (m, 2H), 7.93 (m, 1H), 7.52 (dd,J=7.8, 5.0, 1H), 7.33 (m, 5H), 7.00 (m, 3H), 6.89 (m, 3H), 6.64 (s, 1H),3.83 (t, J=5.5, 2H), 3.30 (m, 8H), 2.90 (m, 2H), 1.86 (m, 2H); MS (EI)m/z 409 (M⁺+1).

Example 833-{3-[4-(4-Fluorophenyl)piperazin-1-yl]benzylidene}-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 3-(3-iodobenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl

Yield: 53%. ¹H NMR (CD₃OD) δ 8.63 (m, 2H), 7.93 (m, 1H), 7.53 (dd,J=7.8, 5.0, 1H), 7.33 (m, 3H), 7.02 (m, 5H), 6.90 (m, 1H), 6.64 (s, 1H),3.83 (t, J=5.5, 2H), 3.29 (m, 8H), 2.87 (m, 2H), 1.87 (m, 2H); MS (EI)m/z 427 (M⁺+1).

Example 843-(3-piperazin-1-ylbenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl from3-(3-iodobenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl

Yield: 19%. ¹H NMR (CDCl₃) δ 8.61 (bs, 2H), 7.89 (m, 1H), 7.51 (m, 1H),7.26 (m, 2H), 7.07 (m, 1H), 6.88 (m, 1H), 6.70 and 6.61 (two s, 1H tot),3.81 (t, J=5.4, 2H), 3.30 (m, 6H), 3.15 (m, 2H), 2.87 (m, 2H), 1.85 (m,2H); MS (EI) m/z 333 (M⁺+1).

Example 853-{3-[(1S,4S)-2,5-Diazabicyclo[2.2.1]hept-2-yl]benzylidene}-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 3-(3-iodobenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl

Yield: 22%. ¹H NMR (CD₃OD) δ 8.59 (m, 2H), 7.89 (dt J_(d)=7.9,J_(t)=1.8, 1H), 7.49 (m, 1H), 7.32 (m, 1H), 7.22 (t J=7.9, 1H), 6.59 (m,1H), 6.49 (s, 1H), 4.53 (s, 1H), 4.31 (s, 1H), 3.80 (m, 2H), 3.61 (m,1H), 3.28 (m, 2H), 2.84 (m, 2H), 2.14 (m, 1H), 1.96 (m, 1H), 1.82 (m,2H); MS (EI) m/z 345 (M⁺+1).

Example 863-(3-[1,4]Oxazepan-4-ylbenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 3-(3-iodobenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl

Yield: 27%. ¹H NMR (CD₃OD) δ 8.63 (m, 2H), 7.93 (m, 1H), 7.53 (dd,J=7.3, 5.0, 1H), 7.20 (t, J=8.3, 1H), 6.73 (m, 1H), 6.64 (m, 2H), 6.63(s, 1H), 3.81 (m, 4H), 3.64 (m, 6H), 2.89 (m, 2H), 1.98 (m, 2H), 1.86(m, 2H); MS (ED m/z 348 (M⁺+1).

Example 873-[4-(4-Phenylpiperazin-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 3-(4-iodobenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl

Yield: 40%. ¹H NMR (CD₃OD) δ 8.63 (m, 2H), 7.92 (m, 1H), 7.55 (dd,J=7.7, 5.2, 1H), 7.34 (m, 2H), 7.25 (t, J=8.5, 2H), 7.01 (m, 3H), 6.86(m, 1H), 6.63 (s, 1H), 3.80 (m, 2H), 3.43 (m, 3H), 3.30 (m, 6H), 2.95(m, 2H), 1.91 (m, 2H); MS (EI) m/z 409 (M⁺+1).

Example 883-{4-[4-(4-Fluorophenyl)piperazin-1-yl]benzylidene}-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 3-(4-iodobenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl

Yield: 75%. ¹H NMR (CD₃OD) δ 8.61 (m, 2H), 7.89 (dt J_(d)=7.9,J_(t)=1.8, 1H), 7.51 (ddd, J=7.8, 5.0, 0.6, 1H), 7.29 (d, J=8.8, 20,6.97 (m, 7H), 6.56 (s, 1H), 3.75 (t, J=5.5, 2H), 3.36 (m, 4H), 3.17 (m,4H), 2.89 (m, 2H), 1.85 (m, 2H); MS (EI) m/z 427 (M⁺+1).

Example 893-{4-[(1S,4S)-2,5-Diazabicyclo[2.2.1]hept-2-yl]benzylidene}-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 3-(4-iodobenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl

Yield: 64%. ¹H NMR (CDCl₃) δ 8.57 (m, 2H), 7.85 (dt, J_(d)=7.9,J_(t)=1.7, 1H), 7.48 (ddd, J=7.9, 5.0, 0.9, 1H), 7.22 (d, J=8.8, 2H),6.58 (d, J=8.8, 2H), 6.48 (s, 1H), 4.45 (3, 1H), 3.93 (s, 1H), 3.73 (t,J=5.5, 2H), 3.57 (dd, J=9.7, 2.2, 1H), 3.12 (m, 1H), 3.04 (s, 2H), 2.87(m, 2H) 1.98 (m, 1H), 1.85 (m, 3H); MS (EI) m/z 345 (M⁺+1).

Example 903-(4-[1,4]Oxazepan-4-ylbenzlidene)-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 3-(4-iodobenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl

Yield: 46%. ¹H NMR (CD₃OD) δ 8.65 (t, J=3.5, 1H), 8.61 (d, J=1.5, 1H),7.91 (m, 1H), 7.54 (dd, J=7.6, 5.0, 1H), 7.30 (d J=8.8, 2H), 6.77 (d,J=8.8, 2H), 6.62 (s, 1H), 3.78 (m, 4H), 3.66 (s, 5H), 2.94 (m, 2H), 1.94(m, 5H); MS (EI) m/z 348 (M⁺+1).

Example 913-[4-(3-Methylpiperazin-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 3-(4-iodobenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl

Yield: 391%. ¹H NMR (CD₃OD) δ 8.61 (m, 2H), 7.89 (dt J_(d)=8.1,J_(t)=1.7, 1H), 7.51 (ddd, J=7.8, 5.0, 0.6, 1H), 7.27 (d, J=8.8, 2H),6.95 (d, J=8.9, 2H), 6.52 (s, 1H, 3.77 (t, J=5.5, 2H), 3.69 (m, 1H),3.12 (m, 1H), 2.95 (m, 4H), 2.76 (m, 1H), 2.43 (dd, J=12.3, 10.4, 1H),1.85 (m, 2H), 1.17 (d, J=6.4, 3H); MS (EI) m/z 347 (M⁺+1).

Example 923-[4-(2-Methylpiperazin-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 3-(4-iodobenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl

Yield: 10%. ¹H NMR (CDCl₃) δ 8.61 (m, 2H), 7.90 (m, 1H), 7.53 (dd,J=7.8, 4.9, 1H), 7.28 (d, J=8.6, 2H), 6.93 (d, J=8.8, 2H), 6.53 (s, 1H),4.06 (m, 1H), 3.77 (m, 2H), 3.32 (m, 2H), 3.05 (m, 2H), 2.91 (m, 5H),1.87 (m, 2H), 1.08 (d, J=6.5, 3H); MS (ED m/z 347 (++1).

Example 933-[3-(4-Ethylpiperazin-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 3-(3-iodobenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl

Yield: 47%. ¹H NMR (CDCl₃) δ 8.63 (m, 2H), 7.94 (m, 1H), 7.52 (m, 1H),7.28 (t, J=7.8, 1H), 6.96 (m, 1H), 6.89 (m, 2H), 6.63 (s, 1H), 3.83 (t,J=5.4, 2H), 3.32 (m, 2H), 2.88 (m, 2H), 2.80 (m, 3H), 2.66 (q, J=7.4,2H), 2.49 (m, 2H), 1.86 (m, 2H), 1.20 (m, 3H); MS (EI) m/z 361 (M⁺+1).

Example 943-[4-(4-Ethylpiperazin-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 3-(4-iodobenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl

Yield: 77%. ¹H NMR (CD₃OD) δ 8.61 (m, 2H), 7.89 (m, 1H), 7.51 (dd,J=7.6, 4-8, 1H), 7.28 (d, J=8.6, 2H), 6.94 (d, J=8.7, 2H), 6.54 (s, 1H),3.76 (t, J=5.0, 2H), 3.29 (m, 4H), 2.89 (m, 2H), 2.65 (m, 4H), 2.52 (q,J=7.2, 2H), 1.85 (m, 2H), 1.15 (t, J=7.1, 3H); MS (EI) m/z 361 (M⁺+1).

Representative Procedure C: Example 953-[1-(4-Chlorobenzyl)-1H-pyrrol-2-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 3-(1H-pyrrol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl

To a solution of3-(1H-pyrrol-2-ylmethylene)-3,4,5,6-tetrahydro-[2,3′]bipyridinyl[example 4] (0.330 g, 1.40 mmol) in DMF (5 mL) was added NaH (60% oildispersion, 120 mg, 3.00 mmol, 2.1 eq). The mixture was stirred for 5min and was treated with 4-chlorobenzyl chloride (0.450 g, 2.80 mmol, 2eq) via syringe. The mixture was stirred at rt for 15 min and wasquenched with MeOH. The reaction mixture was diluted with water,extracted with ether (2×), and the combined organic layers were driedover magnesium sulfate. The crude product was purified by chromatography[1/1 to 0/1 ethyl acetate/(70/30/1 ethyl acetate/methanol/ammoniumhydroxide)] to provide 130 mg (26%) of product. ¹H NMR (MeOD) δ8.61-8.59 (m, 1H), 8.40 (d, J=1.4, 1H), 7.56-7.52 (m, 1H), 7.36-7.32 (m,1H), 7.18 (d, J=8.4, 2H), 7.06 (d, J=1.4, 1H), 6.63 (d, J=8.3, 2H),6.32-6.28 (m, 2H), 4.95 (s, 2H), 3.69-3.65 (m, 2H), 2.74-2.70 (m, 2H),1.86-1.80 (m, 2H); MS (EI) m/z 363 (M⁺+1).

Using this general procedure the following compounds were prepared:

Example 963-[1-(4-Fluorobenzyl)-1H-pyrrol-2-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 3-(1H-pyrrol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl

Yield: 11%. ¹H NMR (MeOD) δ 8.62-8.59 (m, 1H), 8.40 (d, J=1.6, 1H),7.61-7.57 (m, 1H), 7.41-7.37 (m, 1H), 7.08 (d, J=2.2, 1H), 6.95-6.89 (m,2H), 6.68-6.64 (m, 3H), 6.32-6.30 (m, 2H), 4.97 (s, 2H), 3.71-3.67 (m,2H), 2.76-2.72 (m, 2H), 1.93-1.80 (m, 2H); MS (EI) m/z 346 (M⁺+1).

Example 973-[1-(4-Trifluoromethylbenzyl)-1H-pyrrol-2-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 3-(1H-pyrrol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl

Yield: 31%. ¹H NMR (MeOD) δ 8.58-8.56 (m, 1H), 8.41 (d, J=1.4, 1H),7.51-7.48 (m, 3H), 7.29-7.25 (m, 1H), 7.10-7.09 (m, 1H), 6.83 (d, J=8.0,2H), 6.66-6.65 (m, 1H), 6.35-6.33 (m, 1H), 6.25 (s, 1H), 5.07 (s, 2H),3.69-3.65 (m, 2H), 2.75-2.71 (m, 2H), 1.83-1.78 (m, 2H); MS (EI) m/z 396(M⁺+1).

Example 983-[1-(4-Chlorobenzyl)-1H-pyrazol-3-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 3-(2H-pyrazol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl

MS (EI) m/z 363 (M⁺+1).

Example 993-[1-(4-Fluorobenzyl)-1H-pyrazol-3-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 3-(2H-pyrazol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl

MS (EI) m/z 347 (M⁺+1).

Example 1003-[1-(2,6-Dichlorobenzyl)-1H-pyrrol-2-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 3-(1H-pyrrol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl

Yield: 37%. ¹H NMR (MeOD) δ 8.63-8.59 (m, 2H), 7.91-7.87 (m, 1H),7.54-7.49 (m, 1H), 7.39-7.30 (m, 3H), 6.68 (s, 1H), 6.63-6.62 (m, 1H),6.56 (d, J=2.9, 1H), 6.21-6.19 (m, 1H), 5.10 (s, 2H), 3.76-3.72 (m, 2H),2.83-2.79 (m, 2H), 1.91-1.83 (m, 2H); MS (EI) m/z 397 (M⁺+1).

Example 1013-[1-(3,4-Dichlorobenzyl)-1H-pyrrol-2-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 3-(1H-pyrrol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl

Yield: 3%. ¹H NMR (MeOD) δ 8.59-8.57 (m, 1H), 8.41 (d, J=1.7, 1H),7.56-7.52 (m, 1H), 7.37-7.30 (m, 2H), 7.07 (d, J=1.4, 1H), 6.82 (s, 1H),6.67 (d, J=3.8, 1H), 6.57-6.54 (m, 1H), 6.35-6.33 (m, 1H), 6.21 (s, 1H),5.00 (s, 2H), 3.71-3.68 (m, 2H), 2.78-2.74 (m, 2H), 1.90-1.81 (m, 2H);MS (EI) m/z 396, 398 (M⁺+1).

Example 1023-[1-(4-Trifluoromethoxybenzyl)-1H-pyrrol-2-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 3-(1H-pyrrol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl

Yield: 19%. ¹H NMR (MeOD) δ 8.61-8.59 (m, 1H), 8.42 (d, J=1.8, 1H),7.55-7.51 (m, 1H), 7.35-7.31 (m, 1H), 7.12-708 (m, 3H), 6.74 (d, J=8.5,2H), 6.64 (d, J=3.7, 1H), 6.33-6.30 (m, 2H), 4.99 (s, 2H), 3.69-3.65 (m,2H), 2.74-2.70 (m, 2H), 1.85-1.77 (m, 2H); MS (EI) m/z 412 (M⁺+1).

Example 1033-(1-Biphenyl-4-ylmethyl-1H-pyrrol-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 3-(1H-pyrrol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl

Yield: 6%. ¹H NMR (MeOD) δ 8.56-8.54 (m, 1H), 8.40 (d, J=1.5, 1H),7.58-7.55 (m, 2H), 7.51-7.25 (m, 7H), 7.07 (d, J=1.4, 1H), 6.68 (d,J=8.2, 2H), 6.63-6.61 (m, 1H), 6.37 (s, 1H), 6.33-6.31 (m, 1H), 4.96 (s,2H), 3.65-3.62 (m, 2H), 2.72-2.68 (m, 2H), 1.81-1.78 (m, 2H); MS (EI)m/z 404 (M⁺+1).

Example 1043-[1-(2-Fluorobenzyl)-1H-pyrrol-2-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 3-(1H-pyrrol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl

Yield: 12%. ¹H NMR (MeOD) δ 8.59-8.57 (m, 1H), 8.39 (d, J=1.6, 1H),7.57-7.53 (m, 1H), 7.37-7.32 (m, 1H), 7.28-7.22 (m, 1H), 7.09 (d, J=1.5,1H), 7.03-6.97 (m, 2H), 6.67 (d, J=3.2, 1H), 6.48-6.43 (t, J=7.5, 1H),6.35-6.32 (m, 2H), 5.03 (s, 2M), 3.71-3.67 (m, 2H), 2.79-2.74 (m, 2H),1.89-1.81 (m, 2H); MS (EI) m/z 346 (M⁺+1).

Example 1053-(1-Methylpropyl-1H-pyrrol-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 3-(1H-pyrrol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl

Yield: 4%. ¹H NMR (MeOD) δ 8.65-8.61 (m, 2H), 7.94-7.90 (m, 1H),7.57-7.53 (m, 1H), 6.99-6.97 (m, 1H), 6.58-6.55 (m, 2H), 6.28-6.25 (m,1H), 3.82-3.73 (m, 3H), 2.85-2.80 (m, 2H), 1.94-1.88 (m, 2H), 1.62-1.54(m, 2H), 1.28 (d, J=6.7, 3H), 0.63 (t, J=7.4, 3H); MS (EI) m/z 294(M⁺+1).

Example 1063-(1-Pyridin-4-ylmethyl-1H-pyrrol-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 3-(1H-pyrrol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl

Yield: 55%. ¹H NMR (MeOD) δ 8.59-8.57 (m, 1H), 8.40-8.37 (m, 3H),7.52-7.48 (m, 1H), 7.30-7.25 (m, 1H), 7.11-7.10 (m, 1H), 6.72-6.67 (m,2H), 6.37-6.35 (m, 1H), 6.19 (s, 1H), 5.07 (s, 2H), 3.70-3.66 (m, 2H),2.76-2.72 (m, 2H), 1.86-1.78 (m, 2H); MS (EI) m/z 329 (M⁺+1).

Example 1073-[1-(1-Ethylpropyl)-1H-pyrrol-2-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 3-(1H-pyrrol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl

Yield: 2%. ¹H NMR (MeOD) δ 8.65-8.60 (m, 2H), 7.94-7.90 (m, 1H),7.58-7.53 (m, 1H), 6.94-6.93 (m, 1H), 6.94-6.93 (m, 1H), 6.58-6.57 (m,2H), 6.31-6.29 (m, 1H), 3.76 (t, J=5.3, 2H), 3.53-3.47 (m, 1H),2.85-2.81 (m, 2H), 1.95-1.87 (m, 2H), 1.71-1.54 (m, 4H), 0.59 (t, J=7.3,6H); MS (EI) m/z 308 (M⁺+1).

Example 1083-[1-(2-Chloro-6-fluorobenzyl)-1H-pyrrol-2-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 3-(1H-pyrrol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl

Yield: 38%. ¹H NMR (MeOD) δ 8.64-8.61 (m, 1H), 8.57 (d, J=2.2, 1H),7.86-7.82 (m, 1H), 7.51-7.46 (m, 1H), 7.33-7.26 (m, 1H), 7.16-7.13 (m,1H), 7.02-6.95 (m, 1H), 6.88 (s, 1H), 6.66 (s, 1H), 6.53 (d, J=3.5, 1H),6.21-6.19 (m, 1H), 5.02 (s, 2H), 3.71-3.67 (m, 2H), 2.77-2.73 (m, 2H),1.84-1.80 (m, 2H); MS (EI) m/z 381 (M⁺+1).

Example 1093-(1-Pentafluorophenylmethyl-1H-pyrrol-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 3-(1H-pyrrol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl

Yield: 11%. ¹H NMR (MeOD) δ 8.66-8.64 (m, 1H), 8.56 (s, 1H), 7.90-7.86(m, 1H), 7.55-7.51 (m, 1H), 7.04 (d, J=1.3, 1H), 6.60-6.57 (m, 2H),6.28-6.26 (m, 1H), 5.10 (s, 1H), 3.74-3.70 (m, 2H), 2.79-2.75 (m, 2H),1.91-1.85 (m, 2H); MS (EI) m/z 418 (M⁺+1).

Example 1103-[1-(2,4,5-Trifluorobenzyl)-1H-pyrrol-2-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 3-(1H-pyrrol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl

Yield: 36%. ¹H NMR (MeOD) δ 8.61-8.59 (m, 1H), 8.41 (s, 1H), 7.67-7.63(m, 1H), 7.42-7.38 (m, 1H), 7.13-7.08 (m, 2H), 6.66 (s, 1H), 6.35-6.33(m, 2H), 6.26 (s, 1H), 4.99 (s, 2H), 3.72-3.68 (m, 2H), 2.78-2.76 (m,2H), 1.87-1.83 (m, 2H); MS (EI) m/z 382 (M⁺+1).

Example 1113-(1-Ethyl-1H-pyrazol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 3-(2H-pyrazol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl

Yield: 3%. ¹H NMR (CDCl₃) δ 8.73 (d, J=1.5, 1H), 8.62-8.60 (m, 1H), 7.82(d, J=2.0, 1H), 7.40 (d, J=2.3, 1H), 7.33-7.29 (m, 1H), 6.64 (s, 1H),6.40 (d, J=2.3, 1H), 4.17 (q, J=7.3, 1H), 3.88-3.82 (m, 2H), 2.94-2.89(m, 2H), 1.91-1.84 (m, 2H), 1.48 (t, J=7.3, 3H); MS (EI) m/z 267 (M+1).

Example 1123-[1-(2-Methylpropyl)-1H-pyrazol-3-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 3-(2H-pyrazol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl

Yield: 10%. ¹H NMR (CDCl₃) δ 8.70 (d, J=1.6, 1H), 8.59-8.57 (m, 1H),7.79-7.76 (m, 1H), 7.34 (d, J=2.2, 1H), 7.29-7.26 (m, 1H), 6.61 (s, 1H),6.37 (d, J=2.3, 1H), 3.86 (d, J=7.3, 2H), 3.82-3.79 (m, 2H), 2.91-2.86(m, 2H), 2.24-2.05 (m, 1H), 1.85-1.81 (m, 2H), 0.86 (d, J=6.7, 6H); MS(EI) m/z 295 (M⁺+1).

Example 1133-(1-Cyclopropylmethyl-1H-pyrazol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 3-(2H-pyrazol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl

Yield: 5%. ¹H NMR (CDCl₃) δ 8.72 (d, J=1.5, 1H), 8.61-8.59 (m, 1H),7.81-7.78 (m, 1H), 7.50 (d, J=2.3, 1H), 7.32-7.28 (m, 1H), 6.63 (s, 1H),6.40 (d, J=2.4, 1H), 3.96 (d, J=7.1, 2H), 3.82 (t, J=5.5, 2H), 2.93-2.88(m, 2H), 1.87-1.83 (m, 2H), 1.26-1.22 (m, 1H), 0.64-0.60 (m, 2H),0.38-0.32 (m, 2H); MS (EI) m/z 293 (M⁺+1).

Example 1143-(1-Cyclobutylmethyl-1H-pyrazol-3-ylmethylene)-3,4,5,6-tetrahydro-[2,3′]bipyridinylfrom 3-(2H-pyrazol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl

Yield: 4%. ¹H NMR (CDCl₃) δ 8.62 (d, J=1.5, 1H), 8.50-8.47 (m, 1H),7.71-7.67 (m, 1H), 7.25 (d, J=2.2, 1H), 7.20-7.16 (m, 1H), 6.52 (s, 1H),6.26 (d, J=2.3, 1H), 3.98 (d, J=7.3, 2H), 3.72-3.69 (m, 2H), 2.82-2.77(m, 2H), 2.68-2.61 (m, 1H), 1.97-1.87 (m, 2H), 1.82-1.61 (m, 6H); MS(EI) m/z 307 (M⁺+1).

Example 1153-(1-Cyclohexylmethyl-1H-pyrazol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 3-(2H-pyrazol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl

Yield: 2%. ¹H NMR (CDCl₃) δ 8.72 (d J=1.5, 1H), 8.61-8.59 (m, 1H),7.81-7.78 (m, 1H), 7.33 (d, J=2.2, 1H), 7.32-7.28 (m, 1H), 6.64 (s, 1H),6.38 (d, J=2.3, 1H), 3.90 (d, J=7.3, 2H), 3.84-3.80 (m, 2H), 2.92-2.87(m, 2H), 1.89-1.81 (m, 2H), 1.71-1.54 (m, 5H), 1.23-1.10 (m, 4H),0.98-0.90 (m, 2H); MS (EI) m/z 335 (M⁺+1).

Example 1163-(1-Cyclopentyl-1H-pyrazol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 3-(2H-pyrazol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl

Yield: 2%. ¹H NMR (CDCl₃) δ 8.71 (d, J=1.5, 1H), 8.60-8.58 (m, 1H),7.81-7.77 (m, 1H), 7.40 (d, J=2.3, 1H), 7.31-7.28 (m, 1H), 6.62 (s, 1H),6.35 (d, J=2.4, 1H), 4.63-4.58 (m, 1H), 3.82-3.79 (m, 2H), 2.92-2.87 (m,2H), 2.15-1.63 (m, 10H); MS (EI) m/z 307 (M⁺+1).

Example 1173-[5-Bromo-2-(4-chlorobenzyl)-2H-pyrazol-3-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 3-(2H-pyrazol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl

Yield: 4%. ¹H NMR (CDCl₃) δ 8.75-8.74 (m, 1H), 8.62-8.60 (m, 1H),7.85-7.81 (m, 1H), 7.34-7.29 (m, 4H), 7.17-7.14 (m, 2H), 6.46 (s, 1H),5.24 (s, 2H), 3.86-3.82 (m, 2H), 3.06-3.01 (m, 2H), 1.85-1.78 (m, 2H);MS (EI) m/z 443, 445 (M⁺+1).

Representative Procedure D: Example 1183-{4-[(1S,4S)-5-Ethyl-2,5-Diazabicyclo[2.2.1]hept-2-yl]benzylidene}-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom3-{4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]benzylidene}-3,4,5,6-tetrahydro[2,3′]bipyridinyl

To a solution of the amine (51.6 mg, 0.150 mmol) in acetonitrile (1 mL)was added potassium carbonate (33.3 mg, 0.241, 1.6 eq) and iodoethane(13 μL, 0.16 mmol, 1.1 eq). After 12 h, the reaction mixture wasadsorbed on a bed of silica gel and was purified by chromatography [1/1to 0/1 ethyl acetate/(70/30/1 ethylacetate/methanol/ammonium hydroxide)]to provide 40.6 mg (73%) of the adduct as an oil. Data: ¹H NMR (CD₃OD) δ8.59 (m, 2H), 7.89 (dt, J_(d)=7.8, J_(t)=1.8, 1H), 7.52 (dd, J=7.5, 5.0,1H), 7.26 (d, J=8.7, 2H), 6.74 (d, J=8.8, 2H), 6.51 (s, 1H), 3.75 (t,J=5.4, 2H), 3.61 (m, 2H), 3.53 (t, J=6.3, 2H), 2.91 (q, J=6.4, 2H), 2.76(m, 2H), 2.60 (m, 2H), 2.38 (s, 3H), 2.02 (, 2H), 1.86 (m, 3H); MS (EI)m/z 373 (M⁺+1).

Using this general procedure the following compounds were prepared:

Example 1193-[4-(4-Cyclopropylmethylpiperazin-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom3-[4-(4-piperazin-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl

Yield: 37%. ¹H NMR (CDCl₃) δ 8.74 (m, 1H), 8.62 (m, 1H), 7.81 (dt,J_(d)=7.8, J_(t)=2.0, 1H), 7.32 (dd, J=7.8, 4.9, 1H), 7.25 (d, J=8.8,2H), 6.88 (d, J=8.8, 2H), 6.55 (s, 1H), 3.84 (t, J=5.4, 2H), 3.29 (m,4H), 2.86 (m, 2H), 2.68 (m, 4H), 2.31 (q, J=7.2, 2H), 1.83 (m, 2H), 0.91(m, 1H), 0.53 (m, 2H), 0.12 (m, 2H); MS (EI) m/z 387 (M⁺+1).

Example 1203-[4-(4-Cyclopentylpiperazin-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom3-[4-(4-piperazin-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl

Yield: 31%. ¹H NMR (CDCl₃) δ 8.73 (m, 1H), 8.62 (m, 1H), 7.81 (dt,J_(d)=7.8, J=1.9, 1H), 7.32 (ddd, J=7.9, 4.9, 0.6, 1H), 7.25 (dd, J=7.7,5.3, 2H), 6.89 (dd, J=8.6, 6.1, 2H), 6.55 (s, 1H), 3.85 (m, 2H), 3.25(m, 4H), 2.85 (m, 2H), 2.65 (m, 3H), 2.53 (m, 2H), 1.91-1.55 (m, 10H);MS (EI) m/z 401 (M⁺+1).

Example 1213-{4-[(1S,4S)-5-Methyl-2,5-Diazabicyclo[2.2.1]hept-2-yl]benzylidene}-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom3-{4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]benzylidene}-3,4,5,6-tetrahydro[2,3′]bipyridinyl

Yield: 13%. ¹H NMR (CDCl₃) δ 8.58 (m, 2H), 7.87 (m, 1H), 7.51 (m, 1H),7.23 (two d, J=8.8 ea, 2H), 6.60 (two d, J=8.8 ea, 2H), 6.48 (s, 1H),4.36 (s, 1H), 3.74 (m, 2H), 3.55 (s, 1H), 3.40 (m, 1H), 3.31 (m, 2H),2.80 (m, 4H), 2.38 and 2.37 (two s, 3H), 1.92 (m, 6H); MS (EI) m/z 359(M⁺+1).

Example 1223-{4-[(1S,4S)-5-Cyclopropylmethyl-2,5-Diazabicyclo[2.2.1]hept-2-yl]benzylidene}-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom3-{4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]benzylidene}-3,4,5,6-tetrahydro[2,3′]bipyridinyl

Yield: 49%. ¹H NMR (CD₃OD) δ 8.44 (dd, J=4.9, 1.4, 1H), 8.40 (d, J=1.4,1H), 7.71 (dt, J_(d)=7.9, J_(t)=2.0, 1H), 7.34 (ddd, J=7.8, 5.0, 0.7,1H), 7.08 (d, J=8.7, 2H), 6.44 (d, J=8.8, 2H), 6.34 (s, 1H), 4.25 (s,1H), 3.78 (s, 1H), 3.57 (t, J=5.5, 2H), 3.21 (m, 2H), 2.90 (dd, J=10.2,1.7, 1H), 2.71 (m, 3H), 2.35 (m, 2H), 1.77 (m, 5H), 0.74 (m, 1H), 0.37(m, 2H), 0.02 (m, 2H); MS (EI) m/z 399 (M⁺+1).

Example 1233-[4-(4-Methyl[1,4]diazepan-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom3-[4-([1,4]diazepan-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl

Yield: 16%. ¹H NMR (CD₃OD) δ 8.60 (dd, J=4.9, 1.6, 1H), 8.57 (dd, J=2.1,0.7, 1H), 7.87 (dt, J_(d)=7.8, J_(t)=1.9, 1H), 7.50 (ddd, J=7.8, 4.9,0.7, 1H), 7.22 (d, J=8.7, 2H), 6.58 (d, J=8.8, 2H), 6.48 (s, 1H), 3.74(t, J=5.5, 2H), 3.67 (s, 1H), 3.35 (m, 2H), 2.89 (m, 3H), 2.55 (m, 3H),1.91 (m, 5H), 1.06 (t, J=7.2, 3H); MS (EI) m/z 361 (M⁺+1).

Example 1243-[4-(4-Cyclopropylmethyl[1,4]diazepan-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom3-[4-([1,4]diazepan-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl

Yield: 20%. ¹H NMR (CD₃OD) δ 8.64 (m, 2H), 7.93 (dt, J_(d)=7.8,J_(t)=1.9, 1H), 7.56 (ddd, J=7.2, 4.4, 0.6, 1H), 7.32 (d, J=8.8, 2H),6.80 (d, J=9.0, 2H), 6.61 (s, 1H), 3.76 (m, 4H), 3.57 (t, J=6.2, 2H),3.14 (m, 2H), 2.96 (m, 4H), 2.75 and 2.67 (two d, J=6.9 ea, 2H), 2.10(m, 2H), 1.94 (m, 2H), 1.01 (m, 1H), 0.64 (m, 2H), 0.28 (m, 2H); MS (EI)m/z 401 (M⁺+1).

Example 1253-[4-(4-Cyclopentyl[1,4]diazepan-1-yl)-benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom3-[4-([1,4]diazepan-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl

Yield: 13%. ¹H NMR (CD₃OD) δ 8.59 (m, 2H), 7.84 (m, 1H), 7.46 (dd,J=7.8, 4.9, 1H), 7.25 (d, J=8.4, 2H), 6.71 (d, J=8.8, 2H), 6.51 (s, 1H),3.58 (m, 7H), 3.17 (m, 2H), 2.88 (m, 5H), 2.07 (m, 2H), 1.73 (m, 4H); MS(EI) m/z 415 (M⁺+1).

Example 1263-[4-(4-Isobutyl-[1,4]diazepan-1-yl)-benzylidene]-3,4,5,6-tetrahydro-[2,3′]bipyridinylfrom3-[4-([1,4]diazepan-1-yl)-benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl

Yield: 11%. ¹H NMR (CDCl₃) δ 8.74 (m, 1H), 8.62 (dd, J=4.8, 1.7, 1H),7.81 (dt, J_(d)=7.7, J_(t)=2.1, 1H), 7.32 (ddd, J=5.7, 4.9, 1.1, 1H),7.23 (d, J=8.8, 2H), 6.66 (d, J=8.9, 2H), 6.53 (s, 1H), 3.83 (t, J=5.4,2H), 3.53 (m, 4H), 2.87 (m, 2H), 2.74 (m, 2H), 2.56 (m, 2H), 1.88 (m,6H), 0.87 (d, J=6.6, 6H); MS (EI) m/z 403 (M⁺+1).

Example 1273-{4-[(1S,4S)-5-(2-Methylpropyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]benzylidene}-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom3-{4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]benzylidene}-3,4,5,6-tetrahydro[2,3′]bipyridinyl

Yield: 54%. ¹H NMR (CDCl₃) δ 8.73 (d, J=1.5, 1H), 8.69 (dd, J=4.9, 1.6,1H), 7.95 (dt, J_(d)=7.8, J_(t)=1.9, 1H), 7.40 (dd, J=7.9, 5.0, 1H),7.29 (d, J=8.2, 2H), 6.73 (s, 1H), 6.54 (d, J=8.8, 2H), 4.31 (s, 1H),3.86 (t, J=5.5, 2H), 3.68 (s, 1H), 3.41 (s, 2H), 3.13 (s, 1H), 2.92 (m,3H), 2.60 (m, 1H), 2.35 (m, 2H), 2.11 (m, 1H), 1.92 (m, 3H), 1.67 (m,1H), 0.90 (d, J=6.6, 6H); MS (EI) m/z 401 (M⁺+1).

Example 1283-{4-[(1S,4S)-5-Cyclopentyl-2,5-diazabicyclo[2.2.1]hept-2-yl]benzylidene}-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom3-{4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]benzylidene}-3,4,5,6-tetrahydro[2,3′]bipyridinyl

Yield: 42%. ¹H NMR (CDCl₃) δ 8.73 (s, 2H), 8.00 (m, 2H), 7.45 (dd,J=7.5, 4.8, 1H), 7.35 (d, J=8.6, 2H), 6.82 (s, 1H), 6.61 (d, J=8.7, 2H),4.56 (s, 1H), 4.34 (s, 1H), 3.88 (m, 3H), 3.64 (m, 2H), 3.30 (m, 1H),2.96 (s, 4H), 2.65 (m, 1H), 2.19 (m, 1H), 2.00 (m, 8H); MS (EI) m/z 413(M⁺+1).

Example 1293-[4-(4-Ethyl[1,4]diazepan-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom3-[4-([1,4]diazepan-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl

Yield: 66%. ¹H NMR (CDCl₃) δ 8.72 (d, J=1.6, 1H), 8.67 (dd, J=4.9, 1.6,1H), 7.90 (dt, J_(d)=7.8, J_(t)=1.9, 1H), 7.38 (ddd, J=7.8, 4.9, 0.6,1H), 7.28 (d, J=8.8, 2H), 6.68 (d, J=9.1, 2H), 6.67 (s, 1H), 3.84 (t,J=5.5, 2H), 3.72 (m, 2H), 3.56 (t, J=6.3, 2H), 2.92 (m, 5H), 2.75 (m,4H), 2.15 (m, 2H), 1.90 (m, 2H), 1.18 (t, J=7.1, 3H); MS (EI) m/z 375(M⁺+1).

Representative Procedure E: Example 130Cyclopropyl-{4-[4-(5,6-dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)phenyl]piperazin-1-yl}methanonefrom3-[4-(4-piperazin-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl

To a solution of the amine (95.0 mg, 0.286 mmol) in dichloromethane (1mL) was added pyridine (36 μL, 0.45 mmol, 1.6 eq), cyclopropylcarbonylchloride (33 μL, 0.36 mmol, 1.3 eq), and a crystal ofdimethylaminopyridine. After 20 h, the reaction mixture was adsorbed ona bed of silica gel and was purified by chromatography [1/0 to 1/1 ethylacetate/(70/30/1 ethylacetate/methanol/ammonium hydroxide)] to provide52.7 mg (46%) of the adduct as an oil. Data: ¹H NMR (CD₃OD) δ 8.60 (m,2H), 7.88 (dt, J_(d)=7.8, J_(t)=1.7, 1H), 7.50 (dd, J=7.8, 5.0, 1H),7.28 (d, J=8.7, 2H), 6.95 (d, J=8.7, 2H), 6.52 (s, 1H), 3.88 (m, 2H),3.74 (m, 4H), 3.26 (m, 4H), 2.88 (m, 2H), 1.97 (m, 1H), 1.84 (m, 2H),0.88 (m, 4H); MS (EI) m/z 401 (M⁺+1).

Using this general procedure the following compounds were prepared:

Example 1311-{4-[4-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)phenyl]piperazin-1-yl}propan-1-onefrom3-[4-(4-piperazin-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl

Yield: 47%. ¹H NMR (CD₃OD) δ 8.60 (m, 2H), 7.88 (dt, J_(d)=7.8,J_(t)=1.9, 1H), 7.50 (dd, J=7.8, 5.0, 1H), 7.27 (d, J=8.8, 2H), 6.95 (d,J=8.8, 2H), 6.52 (s, 1H), 3.76 (t, J=5.5, 2H), 3.67 (m, 4H), 3.25 (m,4H), 2.88 (m, 2H), 2.44 (q, J=7.5, 2H), 1.84 (m, 2H), 1.13 (t, J=7.4,3H; MS (EI) m/z 3899 (M⁺+1).

Example 1321-{4-[4-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)phenyl]piperazin-1-yl}-2,2,2-trifluoroethanonefrom3-[4-(4-piperazin-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl

Yield: 42%. ¹H NMR (CDCl₃) δ 8.66 (m, 1H), 8.55 (dd, J=4.9, 1.8, 1H),7.74 (dt, J_(d)=7.8, J_(t)=2.0, 1H), 7.25 (ddd, J=7.8, 4.8, 0.7, 1H),7.19 (d, J=8.7, 2H), 6.82 (d, J=8.8, 2H), 6.49 (s, 1H), 3.78 (m, 5H),3.69 (m, 2H), 3.22 (m, 4H), 2.77 (m, 2H), 1.75 (m, 2H), 1.11 (d, J=6.1,4H); MS (EI) m/z 429 (M⁺+1).

Example 133Cyclopropyl-{(1S,4S)-5-[4-(5,6-dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)phenyl]-2,5-diazabicyclo[2.2.1]hept-2-yl}methanonefrom3-{4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]benzylidene}-3,4,5,6-tetrahydro[2,3′]bipyridinyl

Yield: 59%. ¹H NMR (CDCl₃) δ 8.72 (s, 1H), 8.60 (m, 1H), 7.80 (dt,J_(d)=7.8, J_(t)=1.8, 1H), 7.31 (dd, J=7.7, 4.8, 1H), 7.21 (m, 2H), 6.53(m, 3H), 5.00 (s, 1H), 4.54 (s, 1H), 3.82 (t, J=5.5, 2H), 3.56 (m, 3H),3.24 (m, 1H), 2.85 (m, 2H), 2.02 (m, 3H), 1.82 (m, 2H), 0.92 (m, 2H),0.73 (m, 2H); MS (EI) m/z 413 (M⁺+1).

Example 134Cyclopropyl-{4-[4-(5,6-dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)phenyl][1,4]diazepan-1-yl}methanonefrom3-[4-([1,4]diazepan-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl

Yield: 54%. ¹H NMR (CDCl₃) δ 8.73 (m, 1H), 8.62 (dd, J=4.9, 1.6, 1H),7.81 (dt, J_(d)=7.8, J_(t)=1.0, 1H), 7.31 (dd, J=7.3, 4.8, 1H), 7.23(dd, J=8.9, 2.8, 2H), 6.61 (dd, J=8.9, 1.8, 2H), 6.52 (s, 1H), 3.83 (t,J=5.4, 3H), 3.74 (dd, J=10.1, 4.6, 2H), 3.56 (m, 6H), 2.86 (m, 2H), 2.01(m, 3H), 1.83 (m, 2H), 1.25 (m, 2H), 0.76 (m, 2H); MS (EI) m/z 415(M⁺+1).

Example 1351-{(1S,4S)-5-[4-(5,6-Dihydro-4H-[2,8′]bipyridinyl-3-ylidenemethyl)phenyl]-2,5-diazabicyclo[2.2.1]hept-2-yl}-2,2,2-trifluoroethanonefrom3-{4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]benzylidene}-3,4,5,6-tetrahydro[2,3′]bipyridinyl

Yield: 47%. ¹H NMR (CDCl₃) δ 8.74 (m, 1H), 8.63 (dd, J=4.8, 1.6, 1H),7.82 (m, 1H), 7.33 (dd, J=7.8, 4.9, 1H), 7.27 and 7.23 (two d, J=8.3 ea,2H), 6.55 (s, 1H), 6.53 (d, J=8.5, 2H), 5.08 and 4.84 (two s, 1H tot),4.58 and 4.55 (two s, 1H tot), 3.84 (t, J=5.5, 1H), 3.68 (m, 3H), 3.26(m, 1H), 2.85 (m, 2H), 2.09 (m, 3H), 1.84 (m, 2H); MS (EI) m/z 441(M⁺+1).

Example 1361-{(1S,4S)-5-[4-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)phenyl]-2,5-diazabicyclo[2.2.1]hept-2-yl}propan-1-onefrom3-{4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]benzylidene}-3,4,5,6-tetrahydro[2,3′]bipyridinyl

Yield: 74%. ¹H NMR (CDCl₃) δ 8.73 (s, 1H), 8.62 (dd, J=4.8, 1.5, 1H),7.81 (m, 1H), 7.32 (dd, J=7.8, 4.8, 1H), 7.24 and 7.21 (two d, J=8.5 ea,2H), 6.52 (m, 3H), 5.02 (s, 0.6H), 4.52 (s, 1H), 4.47 (s, 0.4H), 3.84(t, J=5.4, 2H), 3.55 (m, 3H), 3.23 and 3.15 (two d, J=9.0, 1H), 2.86 (m,2H), 2.08 (m, 2H), 1.84 (, 2H), 1.10 (m, 3H); MS (EI) m/z 401 (M⁺+1).

Example 1371-{4-[4-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)phenyl][1,4]diazepan-1-yl}-2,2,2-trifluoroethanonefrom3-[4-([1,4]diazepan-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl

Yield: 49%. ¹H NMR (CDCl₃) δ 8.73 (s, 1H), 8.65 (d, J=3.4, 1H), 7.85 (d,J=7.6, 1H), 7.35 (dd, J=7.5, 4.8, 1H), 7.27 (d, J=7.9, 2H), 6.70 (d,J=7.4, 2H), 6.60 (s, 1H), 3.85 (s, 1H), 3.73 (s, 1H), 3.61 (m, 4H), 3.48(m, 1H), 3.13 (q, J=7.4, 2H), 2.88 (m, 2H), 2.07, (m, 2H), 1.88 (m, 2H),1.32 (m, 3H); MS (EI) m/z 443 (M⁺+1).

Example 1381-{4-[4-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)phenyl][1,4]diazepan-1-yl}propan-1-onefrom3-[4-([1,4]diazepan-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl

Yield: 73%. ¹H NMR (CDCl₃) δ 8.73 (s, 1H), 8.62 (m, 1H), 7.81 (d, J=7.7,1H), 7.32 (dd, J=7.5, 4.8, 1H), 7.23 (d, J=7.2, 2H), 6.68 and 6.67 (twod, J=8.6 ea, 2H), 6.52 (s, 1H), 3.83 (t, J=5.2, 2H), 3.75 (m, 1H), 3.60(m, 6H), 3.41 (m, 2H), 2.86 (s, 2H), 2.34 and 2.26 (two q, J=7.4 ea,2H), 2.00 (m, 3H), 1.84 (m, 2H), 1.17 and 1.08 (two t, J=7.5 ea, 3H); MS(EI) m/z 403 (M⁺+1).

Example 139Cyclopropyl-{(1S,4S)-5-[3-(5,6-dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethy)phenyl]-2,5-diazabicyclo[2.2.1]hept-2-yl}methanonefrom3-{3-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]benzylidene}-3,4,5,6-tetrahydro[2,3′]bipyridinyl

Yield: 30%. ¹H NMR (CDCl₃) δ 8.76 (s, 1H), 8.64 (d, J=3.5, 1), 7.83 (m,1H), 7.34 (dd, J=7.7, 4.9, 1H), 7.15 (m, 2H), 6.70 (d, J=7.6, 1H), 6.61(s, 1H), 6.51 (m, 1H), 6.42 and 6.38 (two s, 1H tot), 5.00 and 4.78 (twos, 1H tot), 4.49 and 4.41 (two s, 1H tot) 3.89 (t, J=5.4, 2H), 3.60 (m,3H), 3.19 (m, 1H), 2.84 (m, 2H), 2.04 and 1.82 (two m, 6H tot), 1.39 (m,1H), 0.94 (m, 2H), 0.73 (m, 2H); MS (EI) m/z 413 (M⁺+1).

Example 1401-{(1S,4S)-5-[3-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)phenyl]-2,5-diazabicyclo[2.2.1]hept-2-yl}-2,2,2-trifluoroethanonefrom3-{3-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]benzylidene}-3,4,5,6-tetrahydro[2,3′]bipyridinyl

Yield: 18%. ¹H NMR (CDCl₃) δ 8.76 (d, J=2.1, 1H), 8.64 (dd, J=4.9, 1.7,1H), 7.83 (m, 1H), 7.29 (m, 4H), 6.68 (m, 2H), 6.38 (s, 1H), 5.06 and4.81 (two s, 1H), 4.52 and 4.49 (two s, 1H), 3.89 (t J=5.6, 3H), 3.68(m, 3H), 3.17 (m, 1H), 2.84 (m, 2H), 1.83 (m, 2H); MS (EI) m/z 441(M⁺+1).

Example 141Cyclopropyl-{4-[3-(5,6-dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)phenyl]-[1,4]diazepan-1-yl}methanonefrom3-[3-([1,4]diazepan-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl

Yield: 38%. ¹H NMR (CDCl₃) δ 8.76 (m, 1H), 8.63 (TA 1H), 7.80 (m, 1H),7.22 (m, 3H), 6.52 (m, 3H), 6.44 and 6.41 (two s, 1H), 4.41 (m, 1H),3.89 (s, 23, 3.60 (m, 1H), 3.51 (s, 2H), 3.10 (m, 1H), 2.82 (s, 2H),2.04 (m, 4H), 1.82 (m, 3H), 1.12 (m, 4H); MS (EI) m/z 415 (M⁺+1).

Example 1421-{4-[3-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)phenyl][1,4]diazepan-1-yl}-2,2,2-trifluoroethanonefrom3-[3-([1,4]diazepan-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl

Yield: 10%. ¹H NMR (CDCl₃) δ8.76 (m, 1H), 8.64 (dd, J=4.9, 1.7, 1H),7.83 (m, 1H), 7.25 (m, 3H), 6.67 (m, 3H), 6.53 (s, 1H), 3.89 (m, 4H),3.69 (m, 2H), 3.58 (m, 3H), 2.84 (m, 3H), 1.84 (m, 4H); MS (EI) m/z 443(M⁺+1).

Example 1431-{4-[3-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)phenyl]-[1,4]diazepan-1-yl}propan-1-onefrom3-[3-([1,4]diazepan-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl

Yield: 23%. ¹H NMR (CDCl₃) δ 8.76 (d, J=0.6, 1H), 8.64 (dd, J=4.8, 1.5,1H), 7.84 (dt, J_(d)=7.8, J_(t)=2.0, 1H), 7.34 (dd, J=7.8, 4.9, 1H),7.22 and 7.20 (two d, J=8.0, 2H), 6.67 and 6.62 (two d, J=7.0, 2H), 6.53(s, 1H), 3.89 (t, J=5.5, 2H), 3.57 (m, 4H), 2.84 (m, 2H), 2.61 (m, 3H),2.36 (m, 2H), 1.89 (m, 4H), 1.15 (t, J=7.4, 3H); MS (EI) m/z 403 (M⁺+1).

Representative Procedure F: Example 1443-(Benzo[1,3]dioxol-5-ylmethylene)-5′-methyl-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 5-methylnicotinic Acid Methyl Ester

Substituted Anabaseine Preparation:

To a solution of diisopropylamine (4.4 mL, 31.4 mmol) in tetrahydrofuran(20 mL) at −78° C. was added a 2.5 M solution of n-butyllithium inhexanes (12 mL, 30 mmol). The solution was allowed to warm to rt over 30min and was re-cooled to −78° C. A solution of1-diethylaminomethyl-piperidin-2-one (3.87 g, 21.0 mmol) intetrahydrofuran (10 mL) was added to the lithium diisopropylamide viasyringe. The reaction mixture was maintained at −78° C. for 1 h and wastreated with a solution of 5-methylnicotinic acid methyl ester (2.12 g,14.0 mmol) in tetrahydrofuran (20 mL) via syringe. The reaction mixturewas allowed to warm to rt and was maintained overnight. The reactionmixture was quenched with water (30 mL) and was extracted with ether (2x). The combined organic layers were dried over magnesium sulfate andconcentrated in vacuo. The residue was purified by chromatography [1/0to 1/1 ethyl acetate/(70/30/1 ethyl acetate/methanol/ammoniumhydroxide)] to provide 560 mg (13%) of1-diethylaminomethyl-3-[hydroxy-(5-methylpyridin-3-yl)methylene]piperidin-2-one.To a solution of the piperidin-2-one (550 mg, 1.8 mmol) in acetone (101mL) was added conc. hydrochloric acid (2 L) and the reaction mixture washeated at 100° C. overnight. The reaction mixture was allowed to cool tort, diluted with isopropyl alcohol, and allowed to stand at 0° C. Theproduct was isolated by filtration, thus providing 400 mg (85%) of5′-methyl-3,4,5,6-tetrahydro[2,3′]bipyridinyl dihydrochloride.

Condensation:

According to procedure A. Data: Yield: 6%. ¹H NMR (CDCl₃) δ 8.52 (d,J=1.8, 1H), 8.46 (d, J=1.4, 1H), 7.63 (s, 1H), 6.84 (s, 1H), 6.80 (s,1H), 6.78 (d, J=1.0, 1H), 6.57 (s, 1H), 5.99 (s, 2H), 3.87-3.83 (m, 2H),2.84-2.79 (m, 2H), 2.37 (s, 3H), 1.85-1.81 (m, 2H); MS (EI) m/z 307(M⁺+1).

Using this general procedure the following compounds were prepared:

Example 1453-(1H-Indol-3-ylmethylene)-5′-methyl-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 5-methylnicotinic Acid Methyl Ester

Yield: 2%. ¹H NMR (CDCl₃) δ 8.57 (s, 1H), 8.46 (s, 1H), 7.69 (s, 1H),7.41 (s, 1H), 7.37 (d, J=8.7, 1H), 7.34 (d, J=8.9, 1H), 7.16 (t, J=7.1,1H), 7.06 (d, J=7.7, 1H), 3.80-3.76 (m, 2H), 2.76-2.72 (m, 2H), 2.36 (s,3H), 1.91-1.83 (m, 2H); MS (EI) m/z 302 (M⁺+1).

Example 1465′-Methyl-3-(1H-pyrrol-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 5-methylnicotinic Acid Methyl Ester

Yield: 8%. ¹H NMR (CDCl₃) δ 9.85 (s, 1H), 8.42 (d, J=1.7, 1H), 8.29 (d,J=1.5, 1H), 7.62 (s, 1H), 6.88 (s, 1H), 6.52 (s, 2H), 6.31 (s, 1H),3.78-3.74 (m, 2H), 2.78-2.73 (m, 2H), 1.88-1.84 (m, 2H); MS (EI) m/z 252(M⁺+1).

Example 1473-(Benzo[1,3]dioxol-5-ylmethylene)-5′-fluoro-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 5-fluoronicotinic Acid Methyl Ester

Yield: 7%. ¹H NMR (CDCl₃) δ 8.54 (s, 1H), 8.48 (d, J=2.3, 1H), 7.57-7.52(m, 1H), 6.83 (s, 1H), 6.81-6.75 (m, 2H), 6.53 (s, 1H), 5.98 (s, 2H),3.87-3.83 (m, 2H), 2.83-2.78 (m, 2H), 1.86-1.77 (m, 2H); MS (EI) m/z 311(M⁺+1).

Example 1485′-Fluoro-3-(1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 5-fluoronicotinic Acid Methyl Ester

Yield: 3%. ¹H NMR (CDCl₃) δ 8.80 (s, 1H), 8.66 (d, J=1.5, 1H), 8.55 (d,J=2.8, 1H), 7.68-7.63 (m, 1H), 7.48-7.42 (m, 3H), 7.25 (t, J=7.1, 1H),7.15 (t, J=7.0, 1H), 6.99 (s, 1H), 3.87-3.83 (m, 2H), 2.83-2.80 (m, 2H),1.94-1.87 (m, 2H); MS (EI) m/z 306 (M⁺+1).

Example 1495′-Fluoro-3-(1H-pyrrol-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 5-fluoronicotinic Acid Methyl Ester

Yield: 2%. ¹H NMR (CDCl₃) δ 8.48 (d, J=2.8, 1H), 8.39 (d, J=2.5, 1H),7.61-7.54 (m, 1H), 6.89 (s, 1H), 6.53 (s, 1H), 6.48 (s, 1H), 6.35 (s,1H), 3.79-3.75 (m, 2H), 2.79-2.75 (m, 2H), 1.88-1.81 (m, 2H); MS (EI)m/z 256 (M⁺+1).

Example 1503-(2,3-Dihydrobenzo[1,4]dioxin-4-ylmethylene)-5′-fluoro-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 5-fluoronicotinic Acid Methyl Ester

Yield: 3%. ¹H NMR (CDCl₃) δ 8.56 (s, 1H), 8.49 (d, J=2.7, 1H), 7.62-7.55(m, 1H), 6.88-6.81 (m, 3H), 6.52 (s, 1H), 4.27 (s, 4H), 3.85-3.82 (m,2H), 2.83-2.79 (m, 2H), 1.84-1.80 (m, 2H); MS (EI) m/z 325 (M⁺+1).

Example 1513-(1-Cyclopropylmethyl-1H-pyrrol-2-ylmethylene)-5′-fluoro-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 5-fluoronicotinic Acid Methyl Ester

Yield: 11%. ¹H NMR (CDCl₃) δ 8.58 (d, J=1.6, 1H), 8.52 (d, J=2.8, 1H),7.61-7.57 (m, 1H), 6.89-6.87 (m, 1H), 6.55 (s, 2H), 6.28-6.26 (m, 1H),3.84-3.81 (m, 2H), 3.58 (d, J=6.6, 2H), 2.81-2.76 (m, 2H), 1.89-1.83 (m,2H), 0.98-0.93 (m, 1H), 0.56-0.49 (m, 2H), 0.14-0.11 (m, 2H); MS (EI)m/z 310 (M⁺+1).

Example 1525′-Fluoro-3-(4-morpholin-4-ylbenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 5-fluoronicotinic Acid Methyl Ester

Yield: 3%. ¹H NMR (CDCl₃) δ 8.56-8.54 (m, 1H), 8.46 (s, 1H), 7.73-7.68(m, 1H), 7.28 (d, J=8.8, 2H), 6.93 (d, J=8.9, 2H), 6.53 (s, 1H),3.82-3.76 (m, 6H), 3.21-3.17 (m, 4H), 2.91-2.87 (m, 2H), 1.89-1.81 (m,2H); MS (EI) m/z 352 (M⁺+1).

Example 1533-(1H-Indol-3-ylmethylene)-6′-trifluoromethyl-3,4,5,6-tetrahydro[2,3′]bipyridinylfrom 6-trifluoromethylnicotinic Acid Methyl Ester

Yield: 6%. ¹H NMR (CDCl₃) δ 8.86 (s, 1H), 8.13 (d, J=7.0, 1H), 7.90 (d,J=7.8, 1H), 7.63 (s, 1H), 7.58 (s, 1H), 7.44 (d, J=8.0, 1H), 7.34 (d,J=8.0, 1H), 7.21 (t, J=7.2, 1H), 7.10 (t, J=7.7, 1H), 6.99 (s, 1H),3.84-3.80 (m, 2H), 2.91-2.87 (m, 2H), 2.20-1.98 (m, 2H); MS (EI) m/z 356(M⁺+1).

Representative Procedure G: Example 1543-(2,3-Dihydrobenzo[1.4]dioxin-6-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylDihydrochloride from 2,3-dihydrobenzo[1,4]dioxine-6-carbaldehyde

To a solution of 249 mg (1.07 mmol) of anabaseine dihydrochloride inabsolute ethanol (5 mL) was added 357 mg (2.17 mmol, 2.0 eq) of thealdehyde and 6 drops of concentrated HCl. The mixture was kept at 60° C.for 14 h and was then diluted with 30 ml of ethyl acetate. The reactionmixture was allowed to cool to rt and the resultant precipitate wascollected by filtration and washed with ethyl acetate to afford 314 mg(78%) of the corresponding product Data: ¹H NMR (DMSO-d₆) δ 8.89 (m,1H), 8.81 (m, 1H), 8.07 (m, 1H), 7.68 (m, 1H), 7.18 (m, 2H), 6.98 (m,1H), 4.28 (m, 4H), 3.78 (m, 2H), 2.95 (m, 2H), 2.03 (m, 2H). MS (EI) m/z307 (M⁺+1).

Using this general procedure the following compounds were prepared:

Example 1553-(5′-Bromo[2,2′]bipyrrolyl-5-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylDihydrochloride from 5′-bromo[2,2′]bithiophenyl-5-carbaldehyde

Yield: 50%. ¹H NMR (DMSO-d₆) δ 8.91 (m, 1H), 8.83 (m, 1H), 8.09 (m, 1H),7.73 (m, 2H), 7.57 (m, 1H), 7.50 (m, 1H), 7.45 (m, 1H), 7.33 (m, 1H),3.77 (m, 2H), 2.92 (m, 2H), 2.13 (m, 2H); MS (EI) m/z 415, 417 (M⁺+1).

Example 1565-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)thiophene-2-carboxylicAcid Dihydrochloride from 5-formylthiophene-2-carboxylic Acid

Yield: 55%. ¹H NMR (DMSO-d₆) δ 8.95 (m, 1H), 8.88 (m, 1H), 8.20 (m, 1H),7.79 (m, 2H), 7.61 (m, 1H), 3.92 (m, 2H), 3.13 (m, 2H), 2.29 (m, 2H); MS(EI) m/z 299 (M⁺+1).

Example 1573-[5-(4-Bromophenyl)thiophen-2-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinylDihydrochloride from 5-(4-bromophenyl)thiophene-2-carbaldehyde

Yield: 50%. ¹H NMR (DMSO-d₆) δ 8.89 (m, 1H), 8.81 (m, 1H), 8.08 (m, 1H),7.82 (m, 2H), 7.72 (m, 3H), 7.42 (m, 2H), 7.02 (s, 1H), 3.78 (m, 2H),3.18 (m, 2H), 2.26 (m, 2H); MS (EI) m/z 393, 395 (M⁺+1).

Example 1583-[1-(Toluene-4-sulfonyl)-1H-indol-3-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinylDihydrochloride from 1-toluenesulfonyl-1H-indole-3-carbaldehyde

Yield: 55%. ¹H NMR (DMSO-d₆) δ 8.92 (m, 2H), 8.32 (m, 1H), 8.13 (m, 1H),8.02 (m, 2H), 7.97 (m, 1H), 7.73 (m, 2H), 7.46 (m, 3H), 7.29 (m, 2H),3.83 (m, 2H), 3.07 (m, 2H), 2.48 (s, 3H), 2.26 (m, 2H) MS (EI) m/z 442(M⁺+1).

Example 1593-[1-Methanesulfonyl-1H-indol-3-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinylDihydrochloride from 1-methanesulfonyl-1H-indole-3-carbaldehyde

Yield: 55%. ¹H NMR (DMSO-d₆) δ 8.94 (m, 1H), 8.89 (m, 1H), 8.15 (m, 2H),7.92 (m, 1H), 7.74 (m, 1H), 7.48 (m, 4H), 3.82 (m, 2H), 3.68 (s, 3H),3.43 (m, 2H), 2.12 (m, 2H); MS (EI) m/z 442 (M⁺+1).

Example 1603-(Thiophen-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylDihydrochloride from thiophene-2-carbaldehyde

Yield: 50%. ¹H NMR (CD₃OD) δ 9.00 (m, 2H), 8.32 (r, 1H), 8.13 (m, 1H),7.90 (m, 1H), 7.67 (m, 2H), 7.33 (m, 1H), 3.90 (m, 2H), 3.10 (m, 2H),2.28 (m, 2H); MS (EI) m/z 255 (M⁺+1).

Example 1613-(5-Propylthiophen-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylDihydrochloride from 5-propylthiophene-2-carbaldehyde

Yield: 50%. ¹H NMR (DMSO-d₆) δ 8.90 (m, 2H), 8.10 (m, 1H), 7.71 (m, 1H),7.40 (m, 1H), 7.21 (m, 1H), 7.04 (m, 1H), 3.75 (m, 2H), 2.90 (m, 4H),2.10 (m, 2H), 1.69 (m, 2H), 0.92 (dd, J=6.0 Hz, 3H); MS (EI) m/z 297(M⁺+1).

Example 1623-(5-Bromothiophen-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylDihydrochloride from 5-bromothiophene-2-carbaldehyde

Yield: 40%. ¹H NMR (DMSO-d₆) δ 8.90 (m, 2H), 8.10 (m, 1H), 7.71 (m, 1H),7.60 (m, 1H), 7.49 (m, 1H), 3.76 (m, 2H), 2.86 (m, 2H), 2.12 (m, 2H); MS(EI) m/z 333, 335 (M⁺+1).

Example 1633-(5-Methythiophen-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylDihydrochloride from 5-methylthiophene-2-carbaldehyde

Yield: 60%. ¹H NMR (DMSO-d₆) δ 8.89 (m, 2H), 8.08 (m, 1H), 7.86 (m, 1H),7.60 (m, 1H), 7.44 (m, 1H), 7.07 (m, 1H), 3.75 (m, 2H), 2.87 (m, 2H),2.59 (s, 3H), 2.11 (m, 2H); MS (EI) m/z 269 (M⁺+1).

Example 1643-(4-Bromothiophen-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylDihydrochloride from 3-bromothiophene-2-carbaldehyde

Yield: 40%. ¹H NMR (DMSO-d₆) δ 8.89 (m, 1H), 8.82 (m, 1H), 8.28 (s, 1H),8.09 (m, 1H), 7.81 (m, 1H), 7.71 (m, 1H), 7.50 (m, 1H), 3.78 (m, 2H),2.89 (m, 2H), 2.13 (m, 2H); MS (EI) m/z 333, 335 (M⁺+1).

Example 1654-[5-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)thiophen-2-yl]phenolDihydrobromide

To a −70° C. solution of3-[5-(4-methoxyphenyl)thiophen-2-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl(20 mg, 0.05 mmol) in anhydrous dichloromethane (5 mL) was added 1.0 MBBr₃ in dichloromethane (0.5 mL). The reaction mixture was maintainedunder an atmosphere of N₂ at rt. for 6 h and an additional 0.5 ml BBr₃solution was added. The reaction mixture was maintained over night andwas quenched with anhydrous methanol (1 mL) at −40° C., and wasconcentrated to 1 ml. This procedure was repeated twice and the residuewas dried under high vacuum. The solid obtained was washed with ethylacetate and was isolated, thus providing 15 mg of an orange solid: ¹HNMR (DMSO-d₆) δ 8.89 (m, 2H), 8.08 (m, 1H), 7.70 (m, 6H), 6.85 (m, 2H),3.76 (m, 2H), 2.97 (m, 2H), 2.13 (m, 2H); MS (EI) m/z 347 (M⁺+1).

Example 1663-(Benzo[b]thiophen-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylDihydrochloride from benzo[b]thiophene-2-carbaldehyde

Yield: 60%. ¹H NMR (DMSO-d₆) δ 8.95 (m, 1H), 8.91 (m, 1H), 8.22 (m, 1H),8.10 (m, 2H), 7.97 (m, 1H), 7.79 (m, 1H), 7.60 (m, 1H), 7.50 (m, 2H),3.82 (m, 2H), 3.07 (m, 2H), 2.15 (m, 2H); MS (EI) m/z 305 (M⁺+1).

Example 1673-(Thiophen-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylDihydrochloride from thiophene-3-carbaldehyde

Yield: 60%. ¹H NMR (DMSO-d₆) δ 8.93 (m, 1H), 8.89 (m, 1H), 8.25 (m, 1H),8.20 (m, 1H), 7.77 (m, 2H), 7.60 (m, 1H), 7.25 (m, 1H), 3.79 (m, 2H),2.97 (m, 2H), 2.06 (m, 2H); MS (EI) m/z 361 (M⁺+1).

Example 1683-(Benzo[b]thiophen-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylDihydrochloride from benzo[b]thiophene-3-carbaldehyde

Yield: 60%. ¹H NMR (DMSO-d₆) δ 8.98 (m, 2H), 8.55 (s, 1H), 8.30 (m, 1H),8.11 (m, 1H), 7.80 (m, 1H), 7.59 (m, 1H), 7.45 (m, 3H), 3.85 (m, 2H),3.06 (m, 2H), 2.09 (m, 2H); MS (EI) m/z 305 (M⁺+1).

Example 1693-(2,3-Dihydrobenzofuran-5-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylDihydrochloride

¹H NMR (DMSO-d₆) δ 8.89 (m, 1H), 8.81 (m, 1H), 8.07 (m, 1H), 7.69 (m,1H), 7.59 (s, 1H), 7.44 (s, 1H), 7.16 (m, 1H), 6.90 (m, 1H), 4.64 (dd,J=9.0, 6.0, 2H), 3.78 (m, 2H), 3.22 (dd, J=9.0, 6.0, 2H), 2.98 (m, 2H),2.04 (m, 2H). MS (EI) m/z 291 (M⁺+1).

Example 1703-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-7-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylDihydrochloride from3,4-dihydro-2H-benzo[b][1,4]dioxepine-7-carbaldehyde

Yield: 81%. ¹H NMR (CD₃OD) δ 9.14 (m, 2H), 8.62 (m, 1H), 8.10 (4, 1H),7.27-7.25 (m, 3H), 7.04 (d, J=8.9, 1H), 4.30 (t, J=5.6, 1H), 4.23 (t,J=5.8, 2H), 3.94 (t, J=5.6, 2H), 3.15-3.11 (m, 2H), 2.26-2.18 (m, 4H);MS (EI) m/z 321 (M⁺+1).

Example 1713-(2,2-Dimethylchroman-6-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylDihydrochloride from 2,2-dimethylchroman-6-carbaldehyde

Yield: 71%. ¹H NMR (CD₃OD) δ 9.20-9.11 (m, 2H), 8.81 (m, 1H), 8.29 (m,1H), 7.50-7.49 (m, 2H), 8.30 (s, 1H), 6.84 (d, J=9.3, 1H), 3.94 (1,J=5.6, 2H), 3.16 (t, J=6.0, 2H), 2.83 (t, J=6.7, 2H), 2.24-2.20 (m, 2H),1.86 (t, J=6.7, 2H), 1.35 (s, 6H); MS (EI) m/z 333 (M⁺+1).

Example 1723-(2,2-Difluorobenzo[1,3]dioxol-5-ylmethylene)-3,4,5,6-tetrahydro[2,3′]binyridinylDihydrochloride from 2,2-difluorobenzo[1,3]dioxole-5-carbaldehyde

Yield: 97%. ¹H NMR (CD₃OD) δ 9.25-9.14 (m, 2H), 8.78-8.75 (m, 1H),8.29-8.20 (m, 1H), 7.56 (d, 1H), 7.49 (dd, J=8.5, 1.5, 1H), 7.41 (s,1H), 7.37 (d, J=8.4, 1H), 4.00 (t, J=5.7, 2H), 3.16-3.11 (m, 2H),2.24-2.20 (m, 2H); MS (EI) m/z 329 (M⁺+1).

Example 1733-(7-Methoxybenzo[1,3]dioxol-5-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylDihydrochloride from 7-methoxybenzo[1,3]dioxole-5-carbaldehyde

Yield: 84%. ¹H NMR (CD₃OD) δ 8.77-8.72 (m, 1H), 8.27 (m, 1H), 7.31 (s,1H), 6.96 (s, 2H), 6.08 (s, 2H), 3.95 (t, J=5.6, 2H), 3.89 (s, 3H),3.17-3.13 (m, 2H), 2.23-2.19 (m, 2H); MS (EI) m/z 323 (M⁺+1).

Example 1743-(Benzo[1,3]dioxol-5-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylDihydrochloride from benzo[1,3]dioxole-5-carbaldehyde

Yield: 78%. ¹H NMR DMSO-d₆) δ 9.00-8.98 (m, 2H), 8.33-8.30 (m, 1H),7.89-7.85 (m, 1H), 7.26 (d, J=1.4, 1H), 7.21 (dd, J=8.4, 1.5, 1H), 7.17(s, 1H), 7.08 (d, J=8.2, 1H), 6.15 (s, 2H), 3.80 (t, J=5.5, 2H), 2.99(t, J=5.8, 2H), 2.07-2.03 (m, 2H); MS (EI) m/z 293 (M⁺+1).

Example 1753-(Benzo[1,3]dioxol-4-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylDihydrochloride from benzo[1,3]dioxole-4-carbaldehyde

Yield: 82%. ¹H NMR (CD₃OD) δ 9.20-9.10 (m, 2H), 8.70-8.60 (m, 1H), 7.30(s, 1H), 7.10-7.00 (m, 1H), 6.95-6.80 (m, 2H), 6.05 (s, 2H), 3.95-3.83(m, 2H), 3.15-3.05 (m, 2H), 2.25-2.15 (m, 2H); MS (EI) m/z 293 (M⁺+1).

Example 176 [³H] MLA Binding

Materials: Rat Brain: Pel-Freez Biologicals, CAT No. 56004-2

-   -   Protease inhibitor cocktail tablet: Roche, CAT No. 1697498

Membrane Preparation

Rat brains in 20 vol (w/v) of ice-cold 0.32 M sucrose with proteaseinhibitors (one tablet per 50 ml,) were homogenized with a polytron for10 sec at setting 11, then centrifuged 10 min at 1000 g, 4° C. Thesupernatant was centrifuged again for 20 min at 20,000 g, 4° C. Thepellets were resuspended in binding buffer (200 mM TRIS-HCl, 20 mMHEPES, pH 7.5, 144 mM NaCl, 1.5 mM KCl, 1 mM MgSO₄, 2 mM CaCl₂, 0.1%(w/v) BSA) and stored membrane prep at −80° C.

For saturation assay, the 200 μl assay mixture in binding buffercontains 200 μg of membrane protein, 0.2 to 44 nM of [³H] MLA. Thenonspecific binding was defined using 1 μM MLA. Competition assay wascarried out with 2 nM [³H] MLA and a desirable range of compounds. Theassay mixture was incubated at 22° C. for 2 hours, then harvested withGF/B filter presoaked with 0.3% PEI in binding buffer using Tomtecharvester. The filter was washed three time with binding buffer and theradioactivity was counted with Trilux.

The preceding examples can be repeated with similar success bysubstituting the generically or specifically described reactants and/oroperating conditions of this invention for those used in the precedingexamples.

While the invention has been illustrated with respect to the productionand of particular compounds, it is apparent that variations andmodifications of the invention can be made without departing from thespirit or scope of the invention.

1. A compound of Formula I:

wherein A is (a) phenyl or pyridyl, each of which is substituted by a 5to 7 membered heterocyclic ring containing an O, S, or N ring atom, andoptionally containing a further N ring atom, wherein the heterocyclicring is fully unsaturated, partially saturated or fully saturated and isunsubstituted or substituted one or more times by alkyl having 1 to 8carbon atoms, halogenated alkyl having 1 to 8 carbon atoms, hydroxyalkylhaving 1 to 8 carbon atoms, alkenyl having 2 to 8 carbon atoms, alkynylhaving 2 to 8 carbon atoms, alkoxy having 1 to 8 carbon atoms,halogenated alkoxy having 1 to 8 carbon atoms, cycloalkyl having 3 to 10carbon atoms, cycloalkylalkyl having 4 to 14 carbon atoms, Ar-alkylwherein alkyl portion has 1 to 8 carbon atoms, Het-alkyl wherein alkylportion has 1 to 8 carbon atoms, COR⁵, COOR⁵, CONR⁵R⁶, halogen, cyano,hydroxyl, NR¹R², nitro, oxo, thio, alkylthio, alkylsulfinyl,alkylsulfonyl, Ar, Het or combinations thereof, wherein the heterocyclicring may be bridged by a divalent alkylene group having 1 to 3 carbonatoms, wherein said phenyl or pyridyl is optionally further substitutedby one or more substituents selected from halogen, alkyl having 1 to 4carbon atoms, alkoxy having 1 to 4 carbon atoms, NR¹R², nitro, hydroxyl,cyano, and or combinations thereof, and wherein said 5 to 7 memberedheterocyclic ring is optionally fused with an aryl group or heteroarylgroup which in each case contains 5 to 10 ring atoms and in which theheteroaryl group contains 1 to 3 hetero atoms each selected from O, S,and N, and wherein said aryl group or heteroaryl group is optionallysubstituted one or more times by alkyl having 1 to 8 carbon atoms,halogenated alkyl having 1 to 8 carbon atoms, hydroxyalkyl having 1 to 8carbon atoms, alkenyl having 2 to 8 carbon atoms, alkynyl having 2 to 8carbon atoms, alkoxy having 1 to 8 carbon atoms, halogenated alkoxyhaving 1 to 8 carbon atoms, cycloalkyl having 3 to 10 carbon atoms,cycloalkylalkyl having 4 to 14 carbon atoms, Ar-alkyl wherein alkylportion has 1 to 8 carbon atoms, Het-alkyl wherein alkyl portion has 1to 8 carbon atoms, COR⁵, COOR⁵, CONR⁵R⁶, halogen, carboxy, cyano,hydroxyl, NR¹R², nitro, oxo, thio, Ar, Het and combinations thereof, (b)phenyl or pyridyl which in each case is fused with a 5 to 7 memberedheterocyclic ring containing 1 to 3 hetero atoms each selected from O,S, and N, to form a bicyclic group wherein the fused heterocyclic ringis fully unsaturated, partially saturated or fully saturated, andwherein said bicyclic group is unsubstituted or substituted one or moretimes by alkyl having 1 to 8 carbon atoms, halogenated alkyl having 1 to8 carbon atoms, hydroxyalkyl having 1 to 8 carbon atoms, alkenyl having2 to 8 carbon atoms, alkynyl having 2 to 8 carbon atoms, alkoxy having 1to 8 carbon atoms, halogenated alkoxy having 1 to 8 carbon atoms,cycloalkyl having 3 to 10 carbon atoms, cycloalkylalkyl having 4 to 14carbon atoms, COR⁵, COOR⁵, CONR⁵R⁶, halogen, carboxy, cyano, hydroxyl,NR¹R², nitro, oxo, thio, alkylthio, alkylsulfinyl, alkylsulfonyl, Ar,Het, Ar-alkyl wherein alkyl portion has 1 to 8 carbon atoms, Het-alkylwherein alkyl portion has 1 to 8 carbon atoms, aroyl having 7 to 15carbon atoms in which the aryl portion can be substituted by halogen,C₁₋₈-alkyl, C₁₋₈-alkoxy, nitro, carboxy, hydroxyl, phenoxy, benzyloxy orcombinations thereof, wherein said phenyl or pyridyl and/or the fused 5to 7 membered heterocyclic ring is optionally further substituted by oneor more substituents selected from halogen, alkyl having 1 to 4 carbonatoms, alkoxy having 1 to 4 carbon atoms, NR¹R², nitro, hydroxyl, cyano,and or combinations thereof, and wherein said 5 to 7 memberedheterocyclic ring is optionally fused with another aryl group orheteroaryl group which in each case contains 5 to 10 ring atoms and inwhich the heteroaryl group contains 1 to 3 hetero atoms each selectedfrom O, S, and N, and wherein said aryl group or heteroaryl group isoptionally substituted one or more times by alkyl having 1 to 8 carbonatoms, halogenated alkyl having 1 to 8 carbon atoms, hydroxyalkyl having1 to 8 carbon atoms, alkenyl having 2 to 8 carbon atoms, alkynyl having2 to 8 carbon atoms, alkoxy having 1 to 8 carbon atoms, halogenatedalkoxy having 1 to 8 carbon atoms, cycloalkyl having 3 to 10 carbonatoms, cycloalkylalkyl having 4 to 14 carbon atoms, Ar-alkyl whereinalkyl portion has 1 to 8 carbon atoms, Het-alkyl wherein alkyl portionhas 1 to 8 carbon atoms, COR⁵, COOR⁵, CONR⁵R⁶, halogen, carboxy, cyano,hydroxyl, NR¹R², nitro, oxo, thio, Ar, Het or combinations thereof, or(c) thienyl, pyrrolyl, dithienyl, pyrazolyl, imidazolyl, oxazolyl,isoxazolyl, triazolyl, thiazolyl, or isothiazolyl, each of which isunsubstituted or substituted one or more times by alkyl having 1 to 8carbon atoms, halogenated alkyl having 1 to 8 carbon atoms, hydroxyalkylhaving 1 to 8 carbon atoms, alkenyl having 2 to 8 carbon atoms, alkynylhaving 2 to 8 carbon atoms, alkoxy having 1 to 8 carbon atoms,halogenated alkoxy having 1 to 8 carbon atoms, cycloalkyl having 3 to 10carbon atoms, cycloalkylalkyl having 4 to 14 carbon atoms, Ar-alkylwherein alkyl portion has 1 to 8 carbon atoms, Het-alkyl wherein alkylportion has 1 to 8 carbon atoms, COR⁵, COOR⁵, CONR⁵R⁶, halogen, carboxy,cyano, hydroxyl, NR¹R², nitro, oxo, thio, Ar, Het or combinationsthereof, wherein said thienyl, pyrrolyl, dithienyl, pyrazolyl,imidazolyl, oxazolyl, isoxazolyl, triazolyl, thiazolyl, or isothiazolylgroup is optionally fused with another aryl group or heteroaryl groupwhich in each case contains 5 to 10 ring atoms and in which theheteroaryl group contains 1 to 3 hetero atoms each selected from O, S,and N, and wherein said aryl group or heteroaryl group is optionallysubstituted one or more times by alkyl having 1 to 8 carbon atoms,halogenated alkyl having 1 to 8 carbon atoms, hydroxyalkyl having 1 to 8carbon atoms, alkenyl having 2 to 8 carbon atoms, alkynyl having 2 to 8carbon atoms, alkoxy having 1 to 8 carbon atoms, halogenated alkoxyhaving 1 to 8 carbon atoms, cycloalkyl having 3 to 10 carbon atoms,cycloalkylalkyl having 4 to 14 carbon atoms, Ar-alkyl wherein alkylportion has 1 to 8 carbon atoms, Het-alkyl wherein alkyl portion has 1to 8 carbon atoms, COR⁵, COOR⁵, CONR⁵R⁶, halogen, carboxy, cyano,hydroxyl, NR¹R², nitro, oxo, thio, Ar, Het or combinations thereof; R¹and R² are each independently H, alkyl having 1 to 8 carbon atoms oraryl having 6 to 14 carbon atoms; R³ and R⁴ are each independently H,alkyl having 1 to 8 carbon atoms, halogenated alkyl having 1 to 8 carbonatoms, alkenyl having 2 to 8 carbon atoms, alkynyl having 2 to 8 carbonatoms, alkoxy having 1 to 8 carbon atoms, halogenated alkoxy having 1 to8 carbon atoms, or halogen; R⁵ and R⁶ are each independently H, alkylhaving 1 to 8 carbon atoms, halogenated alkyl having 1 to 8 carbonatoms, alkenyl having 2 to 8 carbon atoms, alkynyl having 2 to 8 carbonatoms, cycloalkyl having 3 to 10 carbon atoms, cycloalkylalkyl having 4to 14 carbon atoms, Ar, Het, Ar-alkyl wherein alkyl portion has 1 to 8carbon atoms, Het-alkyl wherein alkyl portion has 1 to 8 carbon atoms;Ar is an aryl group containing 6 to 14 carbon atoms which isunsubstituted or substituted one or more times by alkyl having 1 to 8 Catoms, alkoxy having 1 to 8 C atoms, halogen, dialkylamino wherein thealkyl portions each have 1 to 8 C atoms, amino, cyano, hydroxyl, nitro,halogenated alkyl having 1 to 8 C atoms, halogenated alkoxy having 1 to8 C atoms, hydroxyalkyl having 1 to 8 C atoms, hydroxyalkoxy having 2 to8 C atoms, alkenyloxy having 3 to 8 C atoms, alkylthio having 1 to 8 Catoms, alkylsulphinyl having 1 to 8 C atoms, alkylsulphonyl having 1 to8 C atoms, monoalkylamino having 1 to 8 C atoms, cycloalkylamino whereinthe cycloalkyl group has 3 to 10 C atoms and is optionally substituted,aryl having 6 to 10 carbon atoms, aryloxy wherein the aryl portioncontains 6 to 14 carbon atoms and is optionally substituted, arylthiowherein the aryl portion contains 6 to 14 carbon atoms and is optionallysubstituted, cycloalkyloxy wherein the cycloalkyl group has 3 to 10 Catoms and is optionally substituted, sulfo, sulfonylamino, acylamido,acyloxy or combinations thereof; and Het is a heterocyclic group, whichis fully saturated, partially saturated or fully unsaturated, having 5to 14 ring atoms in which at least 1 ring atom is a N, O or S atom,which is substituted one or more times by halogen, aryl having 6 to 14carbon atoms and is optionally substituted, e.g., alkyl having 1 to 8 Catoms, alkoxy having 1 to 8 C atoms, cyano, trifluoromethyl, nitro, oxo,amino, monoalkylamino having 1 to 8 C atoms, dialkylamino wherein eachalkyl group has 1 to 8 C atoms, or combinations thereof; or apharmaceutically acceptable salt thereof.
 2. (canceled)
 3. (canceled) 4.(canceled)
 5. (canceled)
 6. (canceled)
 7. (canceled)
 8. (canceled) 9.(canceled)
 10. (canceled)
 11. (canceled)
 12. (canceled)
 13. (canceled)14. (canceled)
 15. (canceled)
 16. (canceled)
 17. (canceled) 18.(canceled)
 19. (canceled)
 20. IA compound according to claim 1, whereinsaid compound is selected from:3-Quinolin-2-ylmethylene-3,4,5,6-terahydro[2,3′]bipyridinyl;3-Quinolin-3-ylmethylene-3,4,5,6-terahydro[2,3′]bipyridinyl;3-(3,4-Dihydroquinolin-4-ylmethylene)-3,4,5,6-terahydro[2,3′]pyridinyl;3-[1-(Toluene-4-sulfonyl-1H-indol-4-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-(1H-Indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-(1H-Indol-4-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-(1H-Pyrrol-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl-1H-indole-6-carboxylicacid Methyl Ester;3-(5-Methoxy-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-(1H-Indol-5-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-(6-Benzyloxy-2H-pyrrolo[3,3-c]pyridin-1-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-(1-Methyl-1H-indol-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-(1-Methyl-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-(4-Benzyloxy-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-(2-Methyl-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-(3H-Imidazol-4-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-(1-Methyl-1H-pyrrol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-(5-Fluoro-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-(6-Methyl-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-(7-Methyl-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-(5-Benzyloxy-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-(2-Methyl-5-nitro-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;[5-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)benzofuran-2-yl]phenylmethanone;6-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)chromen-2-one;3-(5′-Bromo-1H,1′H-[2,2′]bipyrrolyl-5-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylDihydrochloride;5-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)-1H-thiophene-2-carboxylicacid Dihydrochloride;3-(2,3-Dihydrobenzo[1,4]dioxin-6-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylDihydrochloride;3-[5-(4-Bromophenyl)-thiophen-2-ylmethylene]-3,4,5,6-tetrahydro-[2,3′]bipyridinylDihydrochloride;3-[1-(Toluene-4-sulfonyl-1H-indol-3-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinylDihydrochloride;3-[1-Methanesulfonyl-1H-indol-3-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinylDihydrochloride;3-(Thiophen-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylDihydrochloride;3-(Benzofuran-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylDihydrochloride;3-(5-Propylthiophen-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylDihydrochloride;3-(5-Bromothiophen-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylDihydrochloride;3-(5-Methylthiophen-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylDihydrochloride;3-(4-Bromothiophen-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylDihydrochloride;4-[5-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)thiophen-2-yl]phenolDihydrobromide;3-(Benzo[b]thiophen-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylDihydrochloride;3-(Thiophen-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylDihydrochloride;3-(Benzo[b]thiophen-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylDihydrochloride;3-(2,3-Dihydrobenzofuran-5-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylDihydrochloride;3-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-7-ylmethylene)-3,4,5,6-tetrahydro-[2,3′]bipyridinylDihydrochloride;3-(2,2-Dimethylchroman-6-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylDihydrochloride;3-(2,2-Difluorobenzo[1,3]dioxol-5-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylDihydrochloride;3-(7-Methoxybenzo[1,3]dioxol-5-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylDihydrochloride;3-(Benzo[1,3]dioxol-5-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-(5-Bromo-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;4-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)-2-nitrophenol;3-(1-Methyl-1H-pyrrol-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)cinnoline;3-(3-Nitro-4-piperidin-1-ylbenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-(4-(Pyrazol-1-yl)benzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;7-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)-4H-benzo[1,4]oxazin-3-one;6-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)-4H-benzo[1,4]oxazin-3-one;3-(3-Morpholin-4-ylbenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-(3-Pyrrolidin-1-ylbenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-[3-(4-Methylpiperazin-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-(Benzo[1,3]dioxol-4-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylDihydrochloride,3-(4-Pyrrolidin-1-yl-benzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl,3-[2-(4-Methylpiperazin-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl,3-(1H-Indazol-6-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl,3-(1H-Indazol-5-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl,3-(2-Morpholin-4-ylbenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl,3-(1H-Benztriazol-5-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl,5-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)-3-dihydrobenzimidazol-2-one,3-(1H-Benzimidazol-5-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl,3-(4-Morpholin-4-yl-benzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl,3-[4-(4-Methylpiperazin-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl,3-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)-10-methyl-10H-phenothiazine,7-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazine,3-(1H-Pyrrolo[2,3-b]pyridin-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl,3-(6-Methoxy-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl,3-(5,6-Dihydro-4H-[2,3′]-bipyridinyl-3-ylidenemethyl)-9-methyl-9H-carbazole,3-(4-Methoxy-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl,3-(7-Methoxy-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl,3-(6-Fluoro-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl,3-(H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyldihydrochloride,3-(H-indol-6-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl,3-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)-9-ethyl-9H-carbazoledihydrochloride,3-(1-Benzyl-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl,3-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)-9-ethyl-9H-carbazole,3-(5-Nitro-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl,3-(5-Chloro-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro-[2,3′]bipyridinyl,3-(3-Nitro-4-pyrrolidin-1-ylbenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-(3-Amino-4-pyrrolidin-1-ylbenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-(3-Amino-4-piperidin-1-ylbenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-(3-Amino-4-morpholin-4-ylbenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-(5-Chloro-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyldihydrochloride;3-(1H-Indazol-4-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-(3-Piperidin-1-ylbenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-(Benzothiazol-5-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-(3,4-Dihydro-2H-benzo[1,4]oxazin-7-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-(3,4-Dihydro-2H-benzo[1,4]oxazin-7-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyltrihydrochloride;3-(4-Cyclopropylmethyl-3,4-dihydro-2H-benzo[1,4]oxazin-7-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-(4-Ethyl-3,4-dihydro-2H-benzo[1,4]oxazin-7-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-(Benzothiazol-6-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-(1-Phenyl-1H-pyrrol-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-[2-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)pyrrol-1-yl]benzonitrile;3-(2-Cyclohexylmethyl-2H-pyrazol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-(2-Cyclopentyl-2H-pyrazol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-[1-(4-Chlorophenyl)-1H-pyrrol-2-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-[1-(4-Trifluoromethoxyphenyl)-1H-pyrrol-2-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-[4-(trans-2,5-Dimethylpiperazin-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;[3-[4-(cis-3,5-Dimethylpiperazin-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-(4-Thiomorpholin-4-yl-benzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-[4-(1-Oxo-1λ4-thiomorpholin-4-yl)-benzylidene]-3,4,5,6-tetrahydro-[2,3′]bipyridinyl;3-[4-(1,1-Dioxo-1λ6-thiomorpholin-4-yl)-benzylidene]-3,4,5,6-tetrahydro-[2,3′]bipyridinyl;3-[4-(2,6-Dimethylmorpholin-4-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-(4-[1,4]Diazepan-1-ylbenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-(4-piperazin-1-ylbenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-[3-(trans-2,5-Dimethylpiperazin-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-[3-(cis-3,5-Dimethylpiperazin-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-(3-Thiomorpholin-4-yl-benzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-[3-(2,6-Dimethylmorpholin-4-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-(3-[1,4]Diazepan-1-ylbenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-[3-(4-Phenylpiperazin-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-{3-[4-(4-Fluorophenyl)piperazin-1-yl]benzylidene}-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-(3-piperazin-1-ylbenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-{3-[(1S,4S)-2,5-Diazabicyclo[2.2.1]hept-2-yl]benzylidene}-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-(3-[1,4]Oxazepan-4-ylbenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-[4-(4-Phenylpiperazin-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-{4-[4-(4-Fluorophenyl)piperazin-1-yl]benzylidene}-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-f{4-[(1S,4S)-2,5-Diazabicyclo[2.2.1]hept-2-yl]benzylidene}-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-(4-[1,4]Oxazepan-4-ylbenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-[4-(3-Methylpiperazin-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-[4-(2-Methylpiperazin-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-[3-(4-Ethylpiperazin-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-[4-(4-Ethylpiperazin-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-[1-(4-Chlorobenzyl)-1H-pyrrol-2-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-[1-(4-Fluorobenzyl)-1H-pyrrol-2-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-[1-(4-Trifluoromethylbenzyl)-1H-pyrrol-2-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-[1-(4-Chlorobenzyl)-1H-pyrazol-3-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-[1-(4-Fluorobenzyl)-1H-pyrazol-3-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-[1-(2,6-Dichlorobenzyl)-1H-pyrrol-2-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-[1-(3,4-Dichlorobenzyl)-1H-pyrrol-2-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-[1-(4-Trifluoromethoxybenzyl)-1H-pyrrol-2-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-(1-Biphenyl-4-ylmethyl-1H-pyrrol-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-[1-(2-Fluorobenzyl)-1H-pyrrol-2-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-(1-Methylpropyl-1H-pyrrol-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-(1-Pyridin-4-ylmethyl-1H-pyrrol-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-[1-(1-Ethylpropyl)-1H-pyrrol-2-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-[1-(2-Chloro-6-fluorobenzyl)-1H-pyrrol-2-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-(1-Pentafluorophenylmethyl-1H-pyrrol-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-[1-(2,4,5-Trifluorobenzyl)-1H-pyrrol-2-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-(1-Ethyl-1H-pyrazol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-[1-(2-Methylpropyl)-1H-pyrazol-3-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-(1-Cyclopropylmethyl-1H-pyrazol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-(1-Cyclobutylmethyl-1H-pyrazol-3-ylmethylene)-3,4,5,6-tetrahydro-[2,3′]bipyridinyl;3-(1-Cyclohexylmethyl-1H-pyrazol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-(1-Cyclopentyl-1H-pyrazol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-[5-Bromo-2-(4-chlorobenzyl)-2H-pyrazol-3-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-[4-(4-Cyclopropylmethylpiperazin-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-[4-(4-Cyclopentylpiperazin-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-{4-[(1S,4S)-5-Methyl-2,5-Diazabicyclo[2.2.1]hept-2-yl]benzylidene}-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-{4-[(1S,4S)-5-Ethyl-2,5-Diazabicyclo[2.2.1]hept-2-yl]benzylidene}-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-{4-[(1S,4S)-5-Cyclopropylmethyl-2,5-Diazabicyclo[2.2.1]hept-2-yl]benzylidene}-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-[4-(4-Methyl[1,4]diazepan-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-[4-(4-Cyclopropylmethyl[1,4]diazepan-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-[4-(4-Cyclopentyl[1,4]diazepan-1-yl)-benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl3-[4-(4-Isobutyl-[1,4]diazepan-1-yl)-benzylidene]-3,4,5,6-tetrahydro-[2,3′]bipyridinyl;3-{4-[(1S,4S)-5-(2-Methylpropyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]benzylidene}-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-{4-[(1S,4S)-5-Cyclopentyl-2,5-diazabicyclo[2.2.1.]hept-2-yl]benzylidene}-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-[4-(4-Ethyl[1,4]diazepan-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;Cyclopropyl-{4-[4-(5,6-dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)phenyl]piperazin-1-yl}methanone;1-{4-[4-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)phenyl]piperazin-1-yl}propan-1-one;1-{4-[4-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)phenyl]piperazin-1-yl}-2,2,2-trifluoroethanone;Cyclopropyl-{(1S,4S)-5-[4-(5,6-dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)phenyl]-2,5-diazabicyclo[2.2.1]hept-2-yl}methanone;Cyclopropyl-{4-[4-(5,6-dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)phenyl][1,4]diazepan-1-yl}methanone;1-{(1S,4S)-5-[4-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)phenyl]-2,5-diazabicyclo[2.2.1]hept-2-yl}-2,2,2-trifluoroethanone;1-{(1S,4S)-5-[4-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)phenyl]-2,5-diazabicyclo[2.2.1]hept-2-yl}propan-1-one;1-{4-[4-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)phenyl][1,4]diazepan-1-yl}-2,2,2-trifluoroethanone;1-{4-[4-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)phenyl][1,4]diazepan-1-yl}propan-1-one;Cyclopropyl-{(1S,4S)-5-[3-(5,6-dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)phenyl]-2,5-diazabicyclo[2.2.1]hept-2-yl}methanone;1-{(1S,4S)-5-[3-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)phenyl]-2,5-diazabicyclo[2.2.1]hept-2-yl}-2,2,2-trifluoroethanone;Cyclopropyl-{4-[3-(5,6-dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)phenyl]-[1,4]diazepan-1-yl}methanone;1-{4-[3-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)phenyl][1,4]diazepan-1-yl}-2,2,2-trifluoroethanone;1-{4-[3-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)phenyl]-[1,4]diazepan-1-yl}propan-1-one;3-(Benzo[1,3]dioxol-5-ylmethylene)-5′-methyl-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-(1H-Indol-3-ylmethylene)-5′-methyl-3,4,5,6-tetrahydro[2,3′]bipyridinyl;5′-Methyl-3-(1H-pyrrol-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-(Benzo[1,3]dioxol-5-ylmethylene)-5′-fluoro-3,4,5,6-tetrahydro[2,3′]bipyridinyl;5′-Fluoro-3-(1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;5′-Fluoro-3-(1H-pyrrol-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-(2,3-Dihydrobenzo[1,4]dioxin-6-ylmethylene)-5′-fluoro-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-(1-Cyclopropylmethyl-1H-pyrrol-2-ylmethylene)-5′-fluoro-3,4,5,6-tetrahydro[2,3′]bipyridinyl;5′-Fluoro-3-(4-morpholin-4-ylbenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-(1H-Indol-3-ylmethylene)-6′-trifluoromethyl-3,4,5,6-tetrahydro[2,3′];and physiologically acceptable salts thereof.
 21. A compound of FormulaI′:

wherein A is (a) phenyl or pyridyl, each of which is substituted by a 5to 7 membered heterocyclic ring containing an O, S, or N ring atom, andoptionally containing a further N ring atom, wherein the heterocyclicring is fully unsaturated, partially saturated or fully saturated and isunsubstituted or substituted one or more times by alkyl having 1 to 8carbon atoms, halogenated alkyl having 1 to 8 carbon atoms, hydroxyalkylhaving 1 to 8 carbon atoms, alkenyl having 2 to 8 carbon atoms, alkynylhaving 2 to 8 carbon atoms, alkoxy having 1 to 8 carbon atoms,halogenated alkoxy having 1 to 8 carbon atoms, halogen, carboxy, cyano,hydroxyl, NR¹R², nitro, oxo, thio, Ar, Het or combinations thereof,wherein said phenyl or pyridyl is optionally further substituted by oneor more substituents selected from halogen, alkyl having 1 to 4 carbonatoms, alkoxy having 1 to 4 carbon atoms, NR¹R², nitro, hydroxyl, andcyano, and wherein said 5 to 7 membered heterocyclic ring is optionallyfused with an aryl group or heteroaryl group containing 5 to 10 ringatoms in which the heteroaryl group contains 1 to 3 hetero atoms eachselected from O, S, and N, and wherein said aryl group or heteroarylgroup is optionally substituted one or more times by alkyl having 1 to 8carbon atoms, halogenated alkyl having 1 to 8 carbon atoms, hydroxyalkylhaving 1 to 8 carbon atoms, alkenyl having 2 to 8 carbon atoms, alkynylhaving 2 to 8 carbon atoms, alkoxy having 1 to 8 carbon atoms,halogenated alkoxy having 1 to 8 carbon atoms, halogen, carboxy, cyano,hydroxyl, NR¹R², nitro, oxo, thio, Ar, Het and combinations thereof, (b)phenyl or pyridyl which in each case is fused with a 5 to 7 memberedheterocyclic ring containing 1 to 3 hetero atoms each selected from O,S, and N, to form a bicyclic group wherein the fused heterocyclic ringis fully unsaturated, partially saturated or fully saturated, andwherein said bicyclic group is unsubstituted or substituted one or moretimes by alkyl having 1 to 8 carbon atoms, halogenated alkyl having 1 to8 carbon atoms, hydroxyalkyl having 1 to 8 carbon atoms, alkenyl having2 to 8 carbon atoms, alkynyl having 2 to 8 carbon atoms, alkoxy having 1to 8 carbon atoms, halogenated alkoxy having 1 to 8 carbon atoms,halogen, carboxy, cyano, hydroxyl, NR¹R², nitro, oxo, thio, alkylthio,alkylsulfinyl, alkylsulfonyl, aryl having 6 to 10 carbon atoms,arylalkyl having 7 to 14 carbon atoms, aroyl having 7 to 15 carbon atomsin which the aryl portion can be substituted by halogen, C₁₋₈-alkyl,C₁₋₈-alkoxy, nitro, carboxy, hydroxyl, phenoxy, benzyloxy orcombinations thereof, wherein said phenyl or pyridyl and/or the fused 5to 7 membered heterocyclic ring is optionally further substituted by oneor more substituents selected from halogen, alkyl having 1 to 4 carbonatoms, alkoxy having 1 to 4 carbon atoms, NR¹R², nitro, hydroxyl, andcyano, and wherein said 5 to 7 membered heterocyclic ring is optionallyfused with another aryl group or heteroaryl group containing 5 to 10ring atoms in which the heteroaryl group contains 1 to 3 hetero atomseach selected from O, S, and N, and wherein said aryl group orheteroaryl group is optionally substituted one or more times by alkylhaving 1 to 8 carbon atoms, halogenated alkyl having 1 to 8 carbonatoms, hydroxyalkyl having 1 to 8 carbon atoms, alkenyl having 2 to 8carbon atoms, alkynyl having 2 to 8 carbon atoms, alkoxy having 1 to 8carbon atoms, halogenated alkoxy having 1 to 8 carbon atoms, halogen,carboxy, cyano, hydroxyl, NR¹R², nitro, oxo, thio, Ar, Het orcombinations thereof, or (c) thienyl, pyrrolyl, dithienyl, pyrazolyl,imidazolyl, oxazolyl, isoxazolyl, triazolyl, thiazolyl, or isothiazolyl,each of which is unsubstituted or substituted one or more times by alkylhaving 1 to 8 carbon atoms, halogenated alkyl having 1 to 8 carbonatoms, hydroxyalkyl having 1 to 8 carbon atoms, alkenyl having 2 to 8carbon atoms, alkynyl having 2 to 8 carbon atoms, alkoxy having 1 to 8carbon atoms, halogenated alkoxy having 1 to 8 carbon atoms, halogen,carboxy, cyano, hydroxyl, NR¹R², nitro, oxo, thio, Ar, Het orcombinations thereof, wherein said thienyl, pyrrolyl, dithienyl,pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, triazolyl, thiazolyl, orisothiazolyl group is optionally fused with another aryl group orheteroaryl group containing 5 to 10 ring atoms in which the heteroarylgroup contains 1 to 3 hetero atoms each selected from O, S, and N, andwherein said aryl group or heteroaryl group is optionally substitutedone or more times by alkyl having 1 to 8 carbon atoms, halogenated alkylhaving 1 to 8 carbon atoms, hydroxyalkyl having 1 to 8 carbon atoms,alkenyl having 2 to 8 carbon atoms, alkynyl having 2 to 8 carbon atoms,alkoxy having 1 to 8 carbon atoms, halogenated alkoxy having 1 to 8carbon atoms, halogen, carboxy, cyano, hydroxyl, NR¹R², nitro, oxo,thio, Ar, Het or combinations thereof; R¹ and R² are each independentlyH, alkyl having 1 to 8 carbon atoms or aryl having 6 to 10 carbon atoms;Ar is an aryl group containing 6 to 14 carbon atoms which isunsubstituted or substituted one or more times by alkyl having 1 to 8 Catoms, alkoxy having 1 to 8 C atoms, halogen, dialkylamino wherein thealkyl portions each have 1 to 8 C atoms, amino, cyano, hydroxyl, nitro,halogenated alkyl having 1 to 8 C atoms, halogenated alkoxy having 1 to8 C atoms, hydroxyalkyl having 1 to 8 C atoms, hydroxyalkoxy having 2 to8 C atoms, alkenyloxy having 3 to 8 C atoms, alkylthio having 1 to 8 Catoms, alkylsulphinyl having 1 to 8 C atoms, alkylsulphonyl having 1 to8 C atoms, monoalkylamino having 1 to 8 C atoms, cycloalkylamino whereinthe cycloalkyl group has 3 to 10 C atoms and is optionally substituted,aryloxy wherein the aryl portion contains 6 to 14 carbon atoms and isoptionally substituted, arylthio wherein the aryl portion contains 6 to14 carbon atoms and is optionally substituted, cycloalkyloxy wherein thecycloalkyl group has 3 to 10 C atoms and is optionally substituted,sulfo, sulfonylamino, acylamido, acyloxy or combinations thereof; andHet is a heterocyclic group, which is fully saturated, partiallysaturated or fully unsaturated, having 5 to 14 ring atoms in which atleast 1 ring atom is a N, O or S atom, which is substituted one or moretimes by halogen, aryl having 6 to 14 carbon atoms and is optionallysubstituted, alkyl having 1 to 8 C atoms, alkoxy having 1 to 8 C atoms,cyano, trifluoromethyl, nitro, oxo, amino, monoalkylamino having 1 to 8C atoms, dialkylamino wherein each alkyl group has 1 to 8 C atoms, orcombinations thereof; or a pharmaceutically acceptable salt thereof. 22.(canceled)
 23. (canceled)
 24. (canceled)
 25. (canceled)
 26. (canceled)27. (canceled)
 28. (canceled)
 29. (canceled)
 30. (canceled) 31.(canceled)
 32. A compound according to claim 21, wherein said compoundis selected from:3-Quinolin-2-ylmethylene-3,4,5,6-terahydro[2,3′]bipyridinyl;3-Quinolin-3-ylmethylene-3,4,5,6-terahydro[2,3′]bipyridinyl;3-(3,4-Dihydroquinolin-4-ylmethylene)-3,4,5,6-terahydro[2,3′]bipyridinyl;3-[1-(Toluene-4-sulfonyl-1H-indol-4-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-(H-Indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-(1H-Indol-4-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-(H-Pyrrol-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl-1H-indole-6-carboxylicacid Methyl Ester;3-(5-Methoxy-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-(1H-Indol-5-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-(6-Benzyloxy-2H-pyrrolo[3,3-c]pyridin-1-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-(1-Methyl-1H-indol-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-Methyl-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-(4-Benzyloxy-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-(2-Methyl-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-(3H-Imidazol-4-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-(1-Methyl-1H-pyrrol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-(5-Fluoro-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-(6-Methyl-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-(7-Methyl-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-(5-Benzyloxy-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-(2-Methyl-5-nitro-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;[5-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)benzofuran-2-yl]phenylmethanone;6-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)chromen-2-one;3-(5′-Bromo-1H,1′H-[2,2′]bipyrrolyl-5-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylDihydrochloride;5-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)-1H-thiophene-2-carboxylicacid Dihydrochloride;3-(2,3-Dihydrobenzo[1,4]dioxin-6-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylDihydrochloride;3-[5-(4-Bromophenyl)-thiophen-2-ylmethylene]-3,4,5,6-tetrahydro-[2,3′]bipyridinylDihydrochloride;3-[1-(Toluene-4-sulfonyl-1H-indol-3-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinylDihydrochloride;3-[1-Methanesulfonyl-1H-indol-3-ylmethylene]-3,4,5,6-tetrahydro[2,3′]bipyridinylDihydrochloride;3-(Thiophen-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylDihydrochloride;3-(Benzofuran-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylDihydrochloride;3-(5-Propylthiophen-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylDihydrochloride;3-(5-Bromothiophen-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylDihydrochloride;3-(5-Methylthiophen-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylDihydrochloride;3-(4-Bromothiophen-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylDihydrochloride;4-[5-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)thiophen-2-yl]phenolDihydrobromide;3-(Benzo[b]thiophen-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylDihydrochloride; 3-(Thiophen-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl Dihydrochloride;3-(Benzo[b]thiophen-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylDihydrochloride;3-(2,3-Dihydrobenzofuran-5-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylDihydrochloride;3-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-7-ylmethylene)-3,4,5,6-tetrahydro-[2,3′]bipyridinylDihydrochloride;3-(2,2-Dimethylchroman-6-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylDihydrochloride;3-(2,2-Difluorobenzo[1,3]dioxol-5-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylDihydrochloride;3-(7-Methoxybenzo[1,3]dioxol-5-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinylDihydrochloride;3-(Benzo[1,3]dioxol-5-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-(5-Bromo-1H-indol-3-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;4-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)-2-nitrophenol;3-(1-Methyl-1H-pyrrol-2-ylmethylene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)cinnoline;3-(3-Nitro-4-piperidin-1-ylbenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-(4-(Pyrazol-1-yl)benzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;7-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)-4H-benzo[1,4]oxazin-3-one;6-(5,6-Dihydro-4H-[2,3′]bipyridinyl-3-ylidenemethyl)-4H-benzo[1,4]oxazin-3-one;3-(3-Morpholin-4-ylbenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-(3-Pyrrolidin-1-ylbenzylidene)-3,4,5,6-tetrahydro[2,3′]bipyridinyl;3-[3-(4-Methylpiperazin-1-yl)benzylidene]-3,4,5,6-tetrahydro[2,3′]bipyridinyl;and physiologically acceptable salts thereof.
 33. (canceled) 34.(canceled)
 35. (canceled)
 36. (canceled)
 37. (canceled)
 38. (canceled)39. A method of treating and/or preventing dementia in an Alzheimer'spatient comprising administering to the patient a therapeuticallyeffective amount of a compound according to claim 1 to inhibit thebinding of an amyloid beta peptide with nAChRs.
 40. A method of treatinga patient for alcohol withdrawal or treating a patient withanti-intoxication therapy comprising administering to the patient aneffective amount of a compound according to claim
 1. 41. A method oftreating a patient to provide for neuroprotection against damageassociated with strokes and ischemia and glutamate-inducedexcitotoxicity comprising administering to the patient an effectiveamount of a compound according to claim
 1. 42. A method of treating apatient suffering from nicotine addiction, pain, jetlag, obesity and/ordiabetes, or a method of inducing smoking cessation in a patientcomprising administering to the patient an effective amount of acompound according to claim
 1. 43. (canceled)
 44. (canceled) 45.(canceled)
 46. A method of treating a patient suffering from dementiaand other conditions with memory loss comprising administering to thepatient an effective amount of a compound according claim
 21. 47. Amethod of treating a patient suffering from memory impairment due tomild cognitive impairment due to aging, Alzheimer's disease,schizophrenia, Parkinson's disease, Huntington's disease, Pick'sdisease, Creutzfeld-Jakob disease, depression, aging, head trauma,stroke, CNS hypoxia, cerebral senility, or multiinfarct dementiacomprising administering an effective amount of a compound according toclaim
 21. 48. A method of treating and/or preventing dementia in anAlzheimer's patient comprising administering to the patient atherapeutically effective amount of a compound according to claim 21 toinhibit the binding of an amyloid beta peptide with nAChRs.
 49. A methodof treating a patient for alcohol withdrawal or treating a patient withanti-intoxication therapy comprising administering to the patient aneffective amount of a compound according to claim
 1. 50. A method oftreating a patient to provide for neuroprotection against damageassociated with strokes and ischemia and glutamate-inducedexcitotoxicity comprising administering to the patient an effectiveamount of a compound according to claim
 21. 51. A method of treating apatient suffering from nicotine addiction, pain, and/or jetlag, or amethod of inducing smoking cessation in a patient comprisingadministering to the patient an effective amount of a compound accordingto claim
 21. 52. A method of treating a patient suffering from mildcognitive impairment (MCI), vascular dementia (VaD), age-associatedcognitive decline (AACD), amnesia associated w/open-heart-surgery,cardiac arrest, and/or general anesthesia, sleep deprivation inducedcognitive impairment, chronic fatigue syndrome, narcolepsy, AIDS-relateddementia, epilepsy-related cognitive impairment, Down's syndrome,Alcoholism related dementia, drug/substance induced memory impairments,Dementia Puglistica (Boxer Syndrome), or animal dementia comprisingadministering to the patient an effective amount of a compound accordingto claim
 21. 53. A method of treating a patient suffering from aninflammatory disease comprising administering to the patient aneffective amount of a compound of Formula I:

wherein A is (c) phenyl or pyridyl, each of which is substituted by a 5to 7 membered heterocyclic ring containing an O, S, or N ring atom, andoptionally containing a further N ring atom, wherein the heterocyclicring is fully unsaturated, partially saturated or fully saturated and isunsubstituted or substituted one or more times by alkyl having 1 to 8carbon atoms, halogenated alkyl having 1 to 8 carbon atoms, hydroxyalkylhaving 1 to 8 carbon atoms, alkenyl having 2 to 8 carbon atoms, alkynylhaving 2 to 8 carbon atoms, alkoxy having 1 to 8 carbon atoms,halogenated alkoxy having 1 to 8 carbon atoms, cycloalkyl having 3 to 10carbon atoms, cycloalkylalkyl having 4 to 14 carbon atoms, Ar-alkylwherein alkyl portion has 1 to 8 carbon atoms, Het-alkyl wherein alkylportion has 1 to 8 carbon atoms, COR⁵, COOR⁵, CONR⁵R⁶, halogen, cyano,hydroxyl, NR¹R², nitro, thio, alkylthio, alkylsulfinyl, alkylsulfonyl,Ar, Het or combinations thereof, wherein the heterocyclic ring may bebridged by a divalent alkylene group having 1 to 3 carbon atoms, whereinsaid phenyl or pyridyl is optionally further substituted by one or moresubstituents selected from halogen, alkyl having 1 to 4 carbon atoms,alkoxy having 1 to 4 carbon atoms, NR¹R², nitro, hydroxyl, cyano, and orcombinations thereof, and wherein said 5 to 7 membered heterocyclic ringis optionally fused with an aryl group or heteroaryl group which in eachcase contains 5 to 10 ring atoms and in which the heteroaryl groupcontains 1 to 3 hetero atoms each selected from O, S, and N, and whereinsaid aryl group or heteroaryl group is optionally substituted one ormore times by alkyl having 1 to 8 carbon atoms, halogenated alkyl having1 to 8 carbon atoms, hydroxyalkyl having 1 to 8 carbon atoms, alkenylhaving 2 to 8 carbon atoms, alkynyl having 2 to 8 carbon atoms, alkoxyhaving 1 to 8 carbon atoms, halogenated alkoxy having 1 to 8 carbonatoms, cycloalkyl having 3 to 10 carbon atoms, cycloalkylalkyl having 4to 14 carbon atoms, Ar-alkyl wherein alkyl portion has 1 to 8 carbonatoms, Het-alkyl wherein alkyl portion has 1 to 8 carbon atoms, COR⁵,COOR⁵, CONR⁵R⁶, halogen, carboxy, cyano, hydroxyl, NR¹R², nitro, oxo,thio, Ar, Het and combinations thereof, (c) phenyl or pyridyl which ineach case is fused with a 5 to 7 membered heterocyclic ring containing 1to 3 hetero atoms each selected from O, S, and N, to form a bicyclicgroup wherein the fused heterocyclic ring is fully unsaturated,partially saturated or fully saturated, and wherein said bicyclic groupis unsubstituted or substituted one or more times by alkyl having 1 to 8carbon atoms, halogenated alkyl having 1 to 8 carbon atoms, hydroxyalkylhaving 1 to 8 carbon atoms, alkenyl having 2 to 8 carbon atoms, alkynylhaving 2 to 8 carbon atoms, alkoxy having 1 to 8 carbon atoms,halogenated alkoxy having 1 to 8 carbon atoms, cycloalkyl having 3 to 10carbon atoms, cycloalkylalkyl having 4 to 14 carbon atoms, COR⁵, COOR⁵,CONR⁵R⁶, halogen, carboxy, cyano, hydroxyl, NR¹R², nitro, oxo, thio,alkylthio, alkylsulfinyl, alkylsulfonyl, Ar, Het, Ar-alkyl wherein alkylportion has 1 to 8 carbon atoms, Het-alkyl wherein alkyl portion has 1to 8 carbon atoms, aroyl having 7 to 15 carbon atoms in which the arylportion can be substituted by halogen, C₁₋₈-alkyl, C₁₋₈-alkoxy, nitro,carboxy, hydroxyl, phenoxy, benzyloxy or combinations thereof, whereinsaid phenyl or pyridyl and/or the fused 5 to 7 membered heterocyclicring is optionally further substituted by one or more substituentsselected from halogen, alkyl having 1 to 4 carbon atoms, alkoxy having 1to 4 carbon atoms, NR¹R², nitro, hydroxyl, cyano, and or combinationsthereof, and wherein said 5 to 7 membered heterocyclic ring isoptionally fused with another aryl group or heteroaryl group which ineach case contains 5 to 10 ring atoms and in which the heteroaryl groupcontains 1 to 3 hetero atoms each selected from O, S, and N, and whereinsaid aryl group or heteroaryl group is optionally substituted one ormore times by alkyl having 1 to 8 carbon atoms, halogenated alkyl having1 to 8 carbon atoms, hydroxyalkyl having 1 to 8 carbon atoms, alkenylhaving 2 to 8 carbon atoms, alkynyl having 2 to 8 carbon atoms, alkoxyhaving 1 to 8 carbon atoms, halogenated alkoxy having 1 to 8 carbonatoms, cycloalkyl having 3 to 10 carbon atoms, cycloalkylalkyl having 4to 14 carbon atoms, Ar-alkyl wherein alkyl portion has 1 to 8 carbonatoms, Het-alkyl wherein alkyl portion has 1 to 8 carbon atoms, COR⁵,COOR⁵, CONR⁵R⁶, halogen, carboxy, cyano, hydroxyl, NR¹R², nitro, oxo,thio, Ar, Het or combinations thereof, or (c) thienyl, pyrrolyl,dithienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, triazolyl,thiazolyl, or isothiazolyl, each of which is unsubstituted orsubstituted one or more times by alkyl having 1 to 8 carbon atoms,halogenated alkyl having 1 to 8 carbon atoms, hydroxyalkyl having 1 to 8carbon atoms, alkenyl having 2 to 8 carbon atoms, alkynyl having 2 to 8carbon atoms, alkoxy having 1 to 8 carbon atoms, halogenated alkoxyhaving 1 to 8 carbon atoms, cycloalkyl having 3 to 10 carbon atoms,cycloalkylalkyl having 4 to 14 carbon atoms, Ar-alkyl wherein alkylportion has 1 to 8 carbon atoms, Het-alkyl wherein alkyl portion has 1to 8 carbon atoms, COR⁵, COOR⁵, CONR⁵R⁶, halogen, carboxy, cyano,hydroxyl, NR¹R², nitro, oxo, thio, Ar, Het or combinations thereof,wherein said thienyl, pyrrolyl, dithienyl, pyrazolyl, imidazolyl,oxazolyl, isoxazolyl, triazolyl, thiazolyl, or isothiazolyl group isoptionally fused with another aryl group or heteroaryl group which ineach case contains 5 to 10 ring atoms and in which the heteroaryl groupcontains 1 to 3 hetero atoms each selected from O, S, and N, and whereinsaid aryl group or heteroaryl group is optionally substituted one ormore times by alkyl having 1 to 8 carbon atoms, halogenated alkyl having1 to 8 carbon atoms, hydroxyalkyl having 1 to 8 carbon atoms, alkenylhaving 2 to 8 carbon atoms, alkynyl having 2 to 8 carbon atoms, alkoxyhaving 1 to 8 carbon atoms, halogenated alkoxy having 1 to 8 carbonatoms, cycloalkyl having 3 to 10 carbon atoms, cycloalkylalkyl having 4to 14 carbon atoms, Ar-alkyl wherein alkyl portion has 1 to 8 carbonatoms, Het-alkyl wherein alkyl portion has 1 to 8 carbon atoms, COR⁵,COOR⁵, CONR⁵R⁶, halogen, carboxy, cyano, hydroxyl, NR¹R², nitro, oxo,thio, Ar, Het or combinations thereof; R¹ and R² are each independentlyH, alkyl having 1 to 8 carbon atoms or aryl having 6 to 14 carbon atoms;R³ and R⁴ are each independently H, alkyl having 1 to 8 carbon atoms,halogenated alkyl having 1 to 8 carbon atoms, alkenyl having 2 to 8carbon atoms, alkynyl having 2 to 8 carbon atoms, alkoxy having 1 to 8carbon atoms, halogenated alkoxy having 1 to 8 carbon atoms, or halogen;R⁵ and R⁶ are each independently H, alkyl having 1 to 8 carbon atoms,halogenated alkyl having 1 to 8 carbon atoms, alkenyl having 2 to 8carbon atoms, alkynyl having 2 to 8 carbon atoms, cycloalkyl having 3 to10 carbon atoms, cycloalkylalkyl having 4 to 14 carbon atoms, Ar, Het,Ar-alkyl wherein alkyl portion has 1 to 8 carbon atoms, Het-alkylwherein alkyl portion has 1 to 8 carbon atoms; Ar is an aryl groupcontaining 6 to 14 carbon atoms which is unsubstituted or substitutedone or more times by alkyl having 1 to 8 carbon atoms, alkoxy having 1to 8 carbon atoms, halogen, dialkylamino wherein the alkyl portions eachhave 1 to 8 carbon atoms, amino, cyano, hydroxyl, nitro, halogenatedalkyl having 1 to 8 carbon atoms, halogenated alkoxy having 1 to 8carbon atoms, hydroxyalkyl having 1 to 8 carbon atoms, hydroxyalkoxyhaving 2 to 8 carbon atoms, alkenyloxy having 3 to 8 carbon atoms,alkylthio having 1 to 8 carbon atoms, alkylsulphinyl having 1 to 8carbon atoms, alkylsulphonyl having 1 to 8 carbon atoms, monoalkylaminohaving 1 to 8 carbon atoms, cycloalkylamino wherein the cycloalkyl grouphas 3 to 10 carbon atoms and is optionally substituted, aryl having 6 to10 carbon atoms, aryloxy wherein the aryl portion contains 6 to 14carbon atoms and is optionally substituted, arylthio wherein the arylportion contains 6 to 14 carbon atoms and is optionally substituted,cycloalkyloxy wherein the cycloalkyl group has 3 to 10 carbon atoms andis optionally substituted, sulfo, sulfonylamino, acylamido, acyloxy orcombinations thereof; and Het is a heterocyclic group, which is fullysaturated, partially saturated or fully unsaturated, having 5 to 14 ringatoms in which at least 1 ring atom is a N, O or S atom, which issubstituted one or more times by halogen, aryl having 6 to 14 carbonatoms and is optionally substituted by alkyl having 1 to 8 carbon atoms,alkoxy having 1 to 8 carbon atoms, cyano, trifluoromethyl, nitro, oxo,amino, monoalkylamino having 1 to 8 carbon atoms, dialkylamino whereineach alkyl group has 1 to 8 carbon atoms, or combinations thereof; or apharmaceutically acceptable salt thereof.